Jiří Petera

Liposomal doxorubicin combined with regional hyperthermia: Reducing systemic toxicity and improving locoregional efficacy in the treatment of solid tumors

Summary Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes increases the therapeutic index, prolongs circulation time and enhances tumor localization. Pegylated liposomal doxorubicin (PLD) is an established therapeutic agent in epithelial ovarian carcinoma (EOC), breast carcinoma or Kaposi’s sarcoma, and PLD administration results in reduction of toxicity. Addition of regional hyperthermia increases liposome extravasation, induces the doxorubicin release from the liposomes, and the combination of hyperthermia and doxorubicin itself may be supra-additive, resulting in enhanced antitumor efficacy in the heated region. Encouraging results have been reported for the combination of PLD and hyperthermia in EOC, breast carcinoma and hepatocellular carcinoma.

High-dose rate brachytherapy in the treatment of penile carcinoma--first experience.

PURPOSE Interstitial low-dose rate brachytherapy (BRT) allows a conservative treatment of T1-T2 penile carcinoma. High-dose rate (HDR) BRT is often considered as a dangerous method for interstitial implants because of higher risk of complications. However, numerous reports suggest that results of HDR-BRT may be comparable to low-dose rate BRT. There are no data available in the literature regarding HDR interstitial BRT for carcinoma of the penis. METHODS AND MATERIALS Ten patients with early penile carcinoma were treated by interstitial hyperfractionated HDR-BRT at the dose of 18 times 3Gy twice daily between years 2002 and 2009. Breast interstitial BRT template was used for fixation and precise geometry reconstruction of stainless hollow needles. RESULTS Median followup was 20 months. Our BRT technique and fractionation schedule was well tolerated by all patients. Acute reaction consisted predominantly of penis edema and Grade 2 radiation mucositis that dissolved during 8 weeks after the treatment. We neither observed any postradiation necrosis nor urethral stenosis. The worst late side effects recorded were mild telanagiectasias in the treatment region. At the last followup, all patients were alive without evidence of the tumor and with fully functional organ. CONCLUSIONS Hyperfractionated interstitial HDR-BRT with 18 times 3 Gy per fraction twice daily is a promising method in selected patients of penile carcinoma and deserves further evaluation in a larger prospective study.

Weekly Paclitaxel Combined with Local Hyperthermia in the Therapy of Breast Cancer Locally Recurrent after Mastectomy – a Pilot Experience

Background: The combination of chemotherapy and hyperthermia (HT) is a promising approach in the treatment of malignant tumors. In the present report we evaluate the efficacy and toxicity of a combination of weekly paclitaxel combined with local hyperthermia in breast cancer. Patients and Methods: 7 patients were treated for inoperable local recurrence of breast cancer after mastectomy, irradiation, and chemotherapy or hormonal therapy. They weekly received paclitaxel (60–80 mg/m²) in 3-h infusions followed by local HT 41–44 °C for 45 min for 6–18 cycles. Results: Objective local response was observed in all treated patients (complete response in 4 patients and partial response in 3 patients). There were no grade 3 or 4 toxicities, neurologic toxicity or hypersensitivity reactions. Local tolerance to this regimen was also good, with only 4 patients developing mild transient erythema. Conclusion: Our experience indicates that the combination of weekly paclitaxel and HT may be effective in the treatment of locally recurrent breast cancer after mastectomy.

Aplastic Anemia as a Cause of Death in a Patient with Glioblastoma Multiforme Treated with Temozolomide

Background:Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported.Case Report and Results:The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications.Conclusion:Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far.ZusammenfassungHintergrund:Die Standardbehandlung des Glioblastoma multiforme ist die postoperative Radiochemotherapie mit Temozolomid, gefolgt von einer 6-monatigen Erhaltungschemotherapie. Schwerwiegende hämatologische Toxizitäten werden selten berichtet.Fallbericht und Ergebnisse:Die Autoren präsentieren den Fall einer 61-jahrigen Patientin mit Glioblastoma multiforme, die mit externer Strahlentherapie und begleitender Temozolomidchemotherapie in Standarddosierung behandelt wurde. Nach Abschluss der Behandlung zeigte die Patientin Symptome einer schweren aplastischen Anämie, die infolge prolongierter Neutro- und Thrombopenie durch infektiöse Komplikationen zum Tode führte.Schlussfolgerung:Letale Komplikationen einer Temozolomidchemotherapie sind selten, bislang wurden insgesamt vier Fälle einer aplastischen Anämie in der Literatur berichtet.

High-Dose-Rate Interstitial Brachytherapy for the Treatment of Penile Carcinoma

Background:Interstitial low-dose-rate (LDR) brachytherapy allows conservative treatment of T1–T2 penile carcinoma. Highdose-rate (HDR) is often considered to be dangerous for interstitial implants because of a higher risk of complications, but numerous reports suggest that results may be comparable to LDR. Nevertheless, there are no data in the literature available regarding HDR interstitial brachytherapy for carcinoma of the penis.Case Report:A 64-year-old man with T1 N0 M0 epidermoid carcinoma of the glans is reported. Interstitial HDR brachytherapy was performed using the stainless hollow needle technique and a breast template for fixation and good geometry. The dose delivered was 18 × 3 Gy twice daily.Results:After 232 days from brachytherapy, the patient was without any evidence of the tumor, experienced no serious radiationinduced complications, and had a fully functional organ.Conclusion:HDR interstitial brachytherapy is feasible in selected case of penis carcinoma, when careful planning and small single fractions are used.Hintergrund:Die interstitielle Low-Dose-Rate-(LDR-)Brachytherapie ermöglicht eine konservative Behandlung von Peniskarzinomen im Stadium T1–T2. Die High-Dose-Rate-(HDR-)Methode gilt in der Praxis oft als gefährlich für die interstitielle Brachytherapie, da ein höheres Komplikationsrisiko befürchtet wird. Mehrere Studien zeigen jedoch, dass die lokale Kontrollrate grundsätzlich zumindest gleich ist wie mit der LDR-Therapie. Zur interstitiellen HDR-Brachytherapie des Peniskarzinoms wurden bisher keine Daten publiziert.Fallbericht:Berichtet wird über einen 64-jährigen Patienten mit einem Plattenepithelkarzinom des Penis T1 N0 M0. Die interstitielle Brachytherapie wurde mit Nadelapplikatoren und Brusttemplate durchgeführt. Die applizierte Dosis betrug 18 × 3 Gy zweimal täglich.Ergebnisse:Der Patient verblieb 232 Tage nach der Brachytherapie ohne Tumor bei völlig funktionsfähigem Organ, ohne dass schwere Strahlenschäden aufgetreten wären.Schlussfolgerung:Die interstitielle Brachytherapie ist im HDR-Verfahren bei ausgewählten Patienten mit Peniskarzinom möglich, wenn eine sorgfältige Planung erfolgt und kleine Einzeldosen verwendet werden.

Pegylated Liposomal Doxorubicin in Combination with Hyperthermia for Treatment of Skin Metastases of Breast Carcinoma: A Case Report

Background: Incorporation of doxorubicin hydrochloride into pegylated liposomes (PLD) may decrease chemotherapy side effects and increase the activity. Hyperthermia could further potentiate its effectiveness. Case Report: A patient with skin metastases of breast carcinoma was treated with intravenous infusion of PLD (Caelyx®) in combination with ultrasound hyperthermia. Each cycle consisted of infusion of 40 mg PLD absolute dose, followed by 2 fractions of hyperthermia 41–43 °C for 45 min 1 and 48 h after infusion. A complete remission was observed after the combination treatment with no significant toxicity. Conclusion: Present observations suggest that the combination of PLD with hyperthermia of skin metastases of breast carcinoma may be an active and well tolerated treatment.

Trends in stage-specific population-based survival of cancer patients in the Czech Republic in the period 2000-2008

BACKGROUND The objective of this study was to assess trends in overall and in stage-specific 5-year relative survival rates of the Czech cancer patients between periods 2000-2004 and 2005-2008. METHODS All Czech cancer patients diagnosed between 1995 and 2008 were included in the analysis. Period analysis was employed to calculate 5-year relative survival for 21 cancers. RESULTS Significant improvements in crude 5-year relative survival for 14 of 21 assessed types of cancer, including the most frequent diagnoses, such as, colorectal, prostate, breast, lung, kidney, pancreatic, and bladder cancer and melanoma, were identified. Moreover, in case of colorectal, lung, and prostate cancer, improvement in stage-specific 5-year relative survival was confirmed as statistically significant for all clinical stages. No diagnosis showed significant decrease in the 5-year relative survival. However, the 5-year relative survival remained poor in patients with metastatic cancers at diagnosis, particularly in case of liver, pancreatic, lung, and oesophageal cancer. CONCLUSIONS The cancer-specific outcomes in the Czech Republic are improving. Nevertheless, despite the overall significant improvement in 5-year relative survival of most of the cancer diagnoses, the high proportion of patients primarily diagnosed with metastatic cancer still represents a substantial challenge for prevention and early detection.

Complete Response of Multiple Melanoma Brain Metastases after Treatment with Temozolomide

Background: Inoperable melanoma brain metastases are usually uniformly fatal, and complete response after cytotoxic therapy is rare. Case report: A patient with multiple inoperable melanoma brain metastases was treated with 6 cycles of oral temozolomide (300 mg once daily over 5 days every 28 days). A complete response was documented by magnetic resonance. Conclusions: The present observation suggests that temozolomide may be an active and well tolerated treatment for malignant melanoma brain metastases.

Carrier Molecules and Extraction of Circulating Tumor DNA for Next Generation Sequencing in Colorectal Cancer

The aims of the study were: i) to compare circulating tumor DNA (ctDNA) yields obtained by different manual extraction procedures, ii) to evaluate the addition of various carrier molecules into the plasma to improve ctDNA extraction recovery, and iii) to use next generation sequencing (NGS) technology to analyze KRAS, BRAF, and NRAS somatic mutations in ctDNA from patients with metastatic colorectal cancer. Venous blood was obtained from patients who suffered from metastatic colorectal carcinoma. For plasma ctDNA extraction, the following carriers were tested: carrier RNA, polyadenylic acid, glycogen, linear acrylamide, yeast tRNA, salmon sperm DNA, and herring sperm DNA. Each extract was characterized by quantitative real-time PCR and next generation sequencing. The addition of polyadenylic acid had a significant positive effect on the amount of ctDNA eluted. The sequencing data revealed five cases of ctDNA mutated in KRAS and one patient with a BRAF mutation. An agreement of 86% was found between tumor tissues and ctDNA. Testing somatic mutations in ctDNA seems to be a promising tool to monitor dynamically changing genotypes of tumor cells circulating in the body. The optimized process of ctDNA extraction should help to obtain more reliable sequencing data in patients with metastatic colorectal cancer.

Cancer in the elderly.

The population in developed countries is aging and the proportion of higher age categories in the age structure is increasing. In the Czech Republic inhabitants aged over 70 years represented 7% of population in the year 1970, 10% in the year 2009 and the expectation for the year 2030 is 25%. This percentage is even higher in more developed countries in Europe and in the USA. The aging of the population unavoidably leads to a growing number of persons diagnosed and living with cancer (Table 1). With improving treatment and better survival of cancer patients also the number of second and third malignancies is rising (Fig. 1). The dynamics of incidence of the most frequent malignant tumors in patients older than 70 years is shown in Fig. 2. These patients represent 30–60% of newly diagnosed malignancies and an even higher percentage of the cancer death rate. The disease stages at diagnosis in patients aged 70+ are shown in Fig. 3. Fig. 1 Incidence: first and second malignancies in patients with colorectal cancer. Fig. 2 Crude incidence range in age category 70+. Fig. 3 Stages of the disease at diagnosis in patients aged 70+, period 2004–2008. Diagnoses are sorted according to proportion of stages 1 and 2. Table 1 Epidemiology of selected cancer diseases. Growing incidence and mortality of malignant diseases in elderly patients together with an aging population brings new, urgent problems into daily oncological practice. Already some past articles in the Reports of Practical Oncology and Radiotherapy have been devoted to this topic.1 The present special issue is concentrated on some important aspects of this subject. Elderly people frequently suffer due to cardiovascular disorders (myocardial infarctions, ischemic coronary disease with reduction of left ventricular function), pulmonary disorders (changes in ventilation and perfusion, chronical obstructive and restrictive changes), nephrologic and urologic complications, decreased bone marrow reserves, and nutrition problems. Comorbidity in these patients has a deep impact on the tolerance of all principal methods of oncological treatment – surgery, radiotherapy and medical therapy. Elder age categories are underrepresented in most of clinical studies. A comprehensive review and analysis is provided by Kazmierska.2 In the absence of sufficient data on tolerance and results of anticancer therapy in senior citizens clinicians frequently indicate less intensive treatment in comparison with general guidelines. But age itself is not contraindicative of curative oncological treatment and older patients with good performance status and minimal comorbidity may the same benefit from an aggressive approach as younger patients, although more complex supportive and psychological care is frequently necessary. In Particular, radiotherapy can be delivered in radical doses, which is supported by the experience of Soumarova3 and the review by Gugic and Strojan4. Site effects of radiotherapy and the influence on the life quality of patients should be considered.5 On the other hand, radiotherapy can substitute systematic treatment in some cases.6 Undertreatment of elder patients with breast cancer may be connected with poorer outcome compared to younger subjects,7 but Tesarova8 presents evidence that older but otherwise healthy women can tolerate standard adjuvant chemotherapy very well and also surgery should not be omitted. The radiotherapy can be delivered in more patient friendly schedules than the common practice offers.9–11 One of the very important conditions of both radical and palliative treatment of elderly patients is adequate nutrition, which can improve the treatment results and quality of life.12 Zadak13 offers a complex insight into the pathogenesis of tumor cachexia and sarcopenia and recommendations for nutritional care of elderly patients. On the other hand it is important to identify frail patients who will not derive benefit from radical procedures and their quality of life will be impaired. Development of simple and reliable tools for tailoring of oncological treatment is an object of contemporary research.14 A part of the patients progress despite treatment or are in a condition that makes an anticancer treatment impossible. The practical experience with a system of palliative care is described by Slovacek et al.15 An adequate social support seems to be a very important aspect of the complex treatment of senior patients.16 One of most difficult decisions in oncology is related to the end of life of oncological patients. The most pressing questions are discussed by Trivedi.17 Like in other fields of medicine, the necessity of better understanding the problems of elderly patients also emerged in oncology. In the year 1999 the International Society of Geriatric Oncology (SIOG) was established with a goal to guarantee progress and practical achievements for geriatric patients and to grant them equal chance of effective treatment as for younger patients. It seems desirable to create oncogeriatric working groups by oncological departments allowing complex treatment of seniors, including internal, nutritive, rehabilitation and psychological aspects and to establish a subspecialisation of oncology – gerontooncology. We hope, that the present issue will contribute to this effort.