Topotecan plus cyclophosphamide in adults with relapsed or refractory pediatric-type sarcoma: a retrospective analysis from the German Sarcoma Medical Oncology Group (AIO).

BACKGROUND: To assess the efficacy and safety of topotecan and cyclophosphamide (TC) in adult patients with pediatric-type sarcoma subtypes who failed induction chemotherapy. PATIENTS AND METHODS: Patients with pediatric sarcoma subtypes, refractory to or relapsed after at least one prior induction chemotherapy, inoperable, ECOG PS 0-2, with measurable, progressive disease (PD), adequate organ functions, who have been treated with TC combination were retrospectively analysed within the AIO and SAREZ/BMBF network. RESULTS: Thirty-nine patients, median age 28 years (18-58), 14 females, 25 males, have been identified. All patients had received induction treatment according to (inter)national study protocols. Second-line TC was applied in 33 patients (≥3rd-line in 6 patients). Twenty-three patients had refractory disease (evidence of PD during induction chemotherapy); 8 patients experienced an early relapse within 6 months as well as 8 patients after more than 24 months (late relapse). A median of 3 cycles (range, 1-6) had been applied and antitumor activity was: CR 2.6 %, PR 7.9 %, and disease stabilisation (SD) 26.3 %. PR lasted 32.8 months and median duration in patients with SD was 5 months (range, 2.0-14.7). The 3/6-months progression-free rates were 43.2 and 18.9 %. CONCLUSIONS: Limited activity was seen in adult pts with refractory or relapsed pediatric-type sarcomas with the regimen which has proven activity in pediatric patients. Adults with refractory small cell sarcoma appear to have a similar dismal outcome as seen in pts with common adult-type histologies; however, a subset of patients has achieved long-lasting remissions on TC resulting in long-term survival.

Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: a randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Treatment of patients with advanced or metastatic esophagogastric adenocarcinoma should not only prolong life but also provide relief of symptoms and improve quality of life (QOL). Esophagogastric adenocarcinoma mainly occurs in elderly patients, but they are underrepresented in most clinical trials and often do not receive effective combination chemotherapy, most probably for fear of intolerance. Using validated instruments, we prospectively assessed QOL within the randomized FLOT65+ phase II trial. METHODS: Within the FLOT65+ trial, a total of 143 patients aged ≥65 years were randomly allocated to receive biweekly oxaliplatin plus 5-fluorouracil (5-FU) continuous infusion and folinic acid (FLO) or the same regimen in combination with docetaxel 50 mg/m(2) (FLOT). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the gastric module STO22 were administered every 8 weeks until progression. Time to definitive deterioration of QOL parameters was analyzed and compared within the treatment arms. RESULTS: The median age of patients was 70 years. Patients receiving FLOT exhibited higher response rates and had improved disease-free and progression-free survival (PFS). The proportions of patients with evaluable baseline EORTC QLQ-C30 and STO22 questionnaires were balanced (83 % in FLOT and 89 % in FLO). Considering evaluable patients with assessable questionnaires (n = 123), neither functioning nor symptom parameters differed significantly in favor of one of the two treatment groups. Particularly, there was no significant difference regarding time to definitive deterioration of global health status/quality of life from baseline (primary endpoint). Notably, patients receiving FLO or FLOT as palliative treatment (n = 98) achieved comparable QOL results. CONCLUSIONS: Although toxicity was higher in patients receiving FLOT, no negative impact of the addition of docetaxel on QOL parameters could be demonstrated. Thus, elderly patients in need of intensified chemotherapy may receive FLOT without compromising patient-reported outcome parameters.

High frequency of MYC gene amplification is a common feature of radiation-induced sarcomas. Further results from EORTC STBSG TL 01/01.

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation-induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation-induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low-level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors.

A non-comparative phase II study of dose intensive chemotherapy with doxorubicin and ifosfamide followed by high dose ICE consolidation with PBSCT in non-resectable, high grade, adult type soft tissue sarcomas.

The objective was to determine the role of dose intensive induction chemotherapy in patients with soft tissue sarcomas (STS) that were considered unresectable. Treatment consisted of 2-3 cycles of doxorubicin (Dox) and ifosfamide (Ifo) followed by high dose chemotherapy with ifosfamide, carboplatin, etoposide (HD-ICE) plus peripheral blood stem cell transplantation (PBSCT). 30 out of 631 consecutive patients, median age 46 years (21-62), with high grade STS were included. 29 patients completed at least 2 cycles of Dox/Ifo. HD-ICE was withheld because of progressive disease (PD) in 5 patients, neurotoxicity in 6 cases, insufficient peripheral blood stem cell (PBSC) mobilization, complete remission (CR) and refusal in 1 patient each. HD-ICE was associated with non-haematological grade III toxicity including emesis, mucositis, fever, neurotoxicity, and transaminase level elevation. Two additional patients attained a partial response after HD-ICE. Overall, 24 of 30 (80%) patients underwent surgery, with complete tumor resections in 19 patients (63% of all patients, 79% of the operated subgroup); however, 2 of these required amputation. After a median follow up period of 50 months in surviving patients (range, 26-120), 5-year PFS and OS rates were 39% and 48%, respectively. Induction chemotherapy plus consolidation HD-ICE is generally feasible, but is associated with significant neurotoxicity. The advantage of HD-ICE over conventional dose chemotherapy plus external beam radiation therapy (EBRT) in non-resectable disease remains unproven.

Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

IMPORTANCE: The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. OBJECTIVE: To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. DESIGN, SETTING, AND PATIENTS: CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. INTERVENTIONS: After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. RESULTS: A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). CONCLUSIONS AND RELEVANCE: Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.

MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema.

Angiosarcomas (AS) are rare vascular malignancies that arise either de novo as primary tumors or secondary to irradiation or chronic lymphedema. The cytogenetics of angiosarcomas are poorly characterized. We applied array-comparative genomic hybridization as a screening method to identify recurrent alterations in 22 cases. Recurrent genetic alterations were identified only in secondary but not in primary AS. The most frequent recurrent alterations were high level amplifications on chromosome 8q24.21 (50%), followed by 10p12.33 (33%) and 5q35.3 (11%). Fluorescence in situ hybridization analysis in 28 primary and 33 secondary angiosarcomas (31 tumors secondary to irradiation, 2 tumors secondary to chronic lymphedema) confirmed high level amplification of MYC on chromosome 8q24.21 as a recurrent genetic alteration found exclusively in 55% of AS secondary to irradiation or chronic lymphedema, but not in primary AS. Amplification of MYC did not predispose to high grade morphology or increased cell turnover. In conclusion, despite their identical morphology, secondary AS are genetically different from primary AS and are characterized by a high frequency of high level amplifications of MYC. This finding may have implications both for the diagnosis and treatment of these tumors.

High dose chemotherapy as salvage treatment for unresectable late relapse germ cell tumors.

PURPOSE: We assessed the activity of high dose chemotherapy in patients with unresectable late relapse germ cell tumors. MATERIALS AND METHODS: A total of 35 patients with late relapse were included in a group of 216 treated with high dose chemotherapy as first or subsequent salvage treatment in a prospective, randomized, multicenter phase III trial comparing single vs sequential high dose chemotherapy. Late relapse was defined as unequivocal evidence of relapse more than 2 years after completion of cisplatin based chemotherapy. All patients were considered to have unresectable, progressive, late relapse germ cell tumors. Responders were scheduled for surgical resection of all residual lesions when technically feasible. RESULTS: We identified 4 late relapse groups, including late relapse in 20 of 35 patients (57%) after first line treatment (group 1), in 4 (11%) after first salvage treatment (group 2), in 4 (11%) after initial and after first salvage treatment (group 3), and in 7 (20%) after first line treatment and salvage treatment with rapid progression thereafter who were randomized to a high dose chemotherapy trial (group 4). Median time to late relapse was 4.7 years (range 2.1 to 18.3) in all groups. Resection of all residual lesions could be done in 15 of 35 patients (43%). At a median followup of 5.6 years (range 1.9 to 8.5) 5 of 35 patients (14%) had no progression, resulting in 15% projected progression-free survival. CONCLUSIONS: Management for unresectable late relapse germ cell tumors remains controversial. High dose chemotherapy followed by resection of all residual lesions can result in long-term remission in individuals.

[Diagnosis and treatment of liver metastases from primary colorectal tumour]. / Diagnostik und Therapie von Lebermetastasen bei kolorektalem Primärtumor.

Contrast-enhanced multislice computer tomography (MSCT) has established itself as the standard tomographic imaging method both for diagnosis and for treatment monitoring of hepatic lesions. To clarify local conditions before partial liver resection, diffusion-weighted magnetic resonance tomography (DWI-MRT) can also provide important additional information. In order to meet the criteria for a R0 resection, a margin of 0.5 mm seems to be sufficient. Neoadjuvant chemotherapy aiming to reduce tumour size can be given in parallel with portal artery embolisation without adversely affecting perioperative morbidity and mortality. As far as the management of primary resectable liver metastases is concerned, there is an urgent need for more studies. Despite the relatively limited evidence, adjuvant chemotherapy is currently more widely favoured in Germany than perioperative chemotherapy. There is also considerable need for studies concerning preoperative therapy in patients with liver metastases that are not (yet) resectable. In KRAS wild-type tumours, high response rates (in terms of a reduction in the size of metastases) are achieved with a cetuximab/chemotherapy combination. Bevacizumab/chemotherapy combinations lead to high rates of pathohistological complete and partial remissions. What the best parameter for judging the success of preoperative therapy is remains unknown, and so comparison studies using survival as a 'hard' endpoint must be carried out.

[Palliative treatment for colorectal cancer]. / Palliative Therapie des kolorektalen Karzinoms.

Before a decision is made to give a particular drug treatment, first of all the best strategy for the individual patient must be determined. In a patient with an aggressive tumour, for whom a secondary curative approach by means of metastasis resection is not an option, the preferred first-line treatment will generally be a triple combination therapy containing bevacizumab - and this is also true in KRAS/BRAF wild-type patients, since the main aim here is to achieve the longest possible survival time with a minimum of side effects. If an epidermal growth factor receptor (EGFR) antibody (cetuximab or panitumumab) is to be used in first-line or later therapy, then the presence of a KRAS mutation must be excluded beforehand. It is very likely sensible also to exclude a BRAF mutation. Second-line treatment after a first-line therapy containing bevacizumab may be a combination chemotherapy or, in patients who are KRAS wild-type (and possibly also BRAF wild-type), irinotecan plus cetuximab. Locoregional treatments such as chemoembolisation, selective internal radiation therapy (SIRT), and stereotactic

Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis.

The biosynthesis of immunoglobulin leads to constitutive endoplasmic reticulum (ER) stress in myeloma cells, which activates the unfolded protein response (UPR). The UPR promotes protein folding by chaperones and increases proteasomal degradation of misfolded protein. Excessive ER stress induces apoptosis and represents a molecular basis for the bortezomib sensitivity of myeloma. Most solid malignancies such as sarcoma, by contrast, are poorly bortezomib sensitive and display low levels of ER stress. We hypothesized that pharmacologic induction of ER stress might sensitize malignancies to bortezomib treatment. We show that the HIV protease inhibitor ritonavir induces ER stress in bortezomib-resistant sarcoma cells. Ritonavir triggered the UPR, decreased the degradation of newly synthesized protein, but did not directly inhibit proteasomal active sites in the therapeutic dose range in contrast to bortezomib. Whereas neither bortezomib nor ritonavir monotherapy translated into significant apoptosis at therapeutic drug levels, the combination strongly increased the level of ER stress and activated PERK, IRE1, and ATF6, synergistically induced CHOP, JNK, caspase-4, and caspase-9, and resulted in >90% apoptosis. In summary, ritonavir increases the level of ER stress induced by bortezomib, which sensitizes bortezomib-resistant cells to bortezomib-induced apoptosis. Ritonavir may therefore be tested clinically to improve the sensitivity of solid malignancies toward bortezomib treatment.

Potential combination chemotherapy approaches for advanced adult-type soft-tissue sarcoma.

Soft-tissue sarcomas (STS) include a spectrum of histologically and clinically different tumors. Patients with these tumors are typically relatively young and the course of disease is characterized by early metastasis as well as limited response to chemotherapy. However, a few subtypes, such as small round-cell tumors and rhabdomyosarcoma (other than pleomorphic), are considered chemotherapy sensitive. In addition, reflecting successful translational research of recent years, gastrointestinal stromal tumor and dermatofibrosarcoma protuberans have become model diseases for targeted oncologic therapy. We summarize current treatment options for metastatic STS, including established first-line chemotherapy approaches, mainly with anthracyclines and/or ifosfamide and second-line treatment choices beyond anthracyclines. Until only a few years ago, treatment choices for metastatic STS were easy to review because of the very limited number of active compounds available. However, with the advent of novel therapeutic strategies such as the anti-angiogenic approach and a multitude of novel compounds available both outside and within clinical studies, it has potentially become more difficult to keep track of currently available treatment options for STS and their clinical safety and efficacy. In this practice-oriented article, we therefore review treatment goals in advanced STS and provide an overview of compounds with proven activity in this setting. Anthracyclines with or without ifosfamide are still considered standard of care for most STS subtypes, especially for high-grade tumors. There is no evidence-based recommendation regarding use of second-line treatment options. However, a number of established compounds, including dacarbazine/temozolomide, gemcitabine, taxanes, trofosfamide, DNA topoisomerase I inhibitors, DNA minor groove binders, and bendamustine have shown activity. Recently, trabectedin, a DNA minor groove binder initially isolated from a sea sponge, has proven effective and received European approval for use in treatment-refractory STS. In addition, novel compounds such as bevacizumab, multi-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, imatinib, and the thrombospondin agonist ABT 510 represent attractive partners for the above-mentioned cytostatic agents, or may even be effective single agents in the clinically advanced setting. Novel combinations are being evaluated in clinical studies. In order to be successful, it may be necessary to combine not only different compounds but also different targets beyond the proliferation machinery of sarcoma cells such as tumor angiogenesis, the tumor stromal compartment, or tumor cell oncogene products.

Mitomycin C in the treatment of gastrointestinal tumours: recent data and perspectives.

Mitomycin C (MMC) is among the most effective anticancer drugs used for the treatment of a broad variety of tumours. This review summarises results of MMC-based chemotherapy in gastrointestinal tumours with special focus on current treatment options in gastric, pancreatic, biliary tract, colorectal, and anal cancer. In addition, these new developments are critically discussed with special attention to their potential clinical relevance.

Gefitinib in combination with oxaliplatin and 5-fluorouracil in irinotecan-refractory patients with colorectal cancer: a phase I study of the Arbeits gemeinschaft Internistische Onkologie (AIO).

BACKGROUND: The aim of the study was to establish the recommended dose and to evaluate the safety of gefitinib plus FUFOX regimen in irinotecan-refractory colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients with advanced CRC progressing on fluoropyrimidine/irinotecan-based chemotherapy and with an ECOG performance level 0-2 were enrolled. Four dose levels with sequential dose escalation of oral gefitinib and FUFOX were tested. Each cycle consisted of 5 weeks with gefitinib given daily to weekly FUFOX x4 to be repeated at day 36. RESULTS: Eighteen patients were enrolled. No dose-limiting toxicity (DLT) was observed at the dose levels L1-L3. At L4 diarrhea was the major DLT requiring treatment interruption in 3 patients. Other grade 3/4 toxicities were observed with skin rash, paresthesia, anemia, and nausea/vomiting (n = 1 each). Grade 1/2 toxicities consisted of diarrhea (n = 9), mucositis (8), skin rash (10), paresthesia (10), nausea (7) as well as leukopenia (2) and fever (1). Clinical benefit was seen in 11 of 16 evaluable patients (69%): 4 patients showed partial response (25%), 7 stable disease (44%). Median time to progression was 219 days (range 50-387 days). CONCLUSION: Gefitinib at a dose of 250 mg daily in combination with weekly 5-fluorouracil at 2,000 mg/m(2) or gefitinib at a dose of 500 mg daily with 5-fluorouracil at 1,600 mg/m(2) plus oxaliplatin has an acceptable safety profile.

[Medical Treatment of Soft Tissue Sarcoma]. / Internistische Therapie von Weichteilsarkomen.

Soft tissue sarcomas are a diagnostically and therapeutically complex disease. This is due to the pronounced heterogeneity, characterized by biologically very different histological subtypes and the resulting clinical progressions. The term encompasses more than 80 different pathologically defined tumors of the soft tissue. Every year, nearly 4000 patients are affected in Germany. The diversity and rarity of the disease make progress difficult. The average 5-year mortality is around 40 %. Therapy is stage-adapted based on size, grading, localization, involvement of lymph nodes or distant metastasis. In the localized situation, surgery is the basis of therapy. Standard is the wide resection. Depending on grading, degree of resection and localization, adjuvant radiotherapy follows in the case of so-called high-risk tumors. Certain very aggressive types (so-called small, blue, round cell sarcomas such as embryonal rhabdomyosarcomas, Ewing tumors, PNET and desmoplastic soft tissue sarcomas (desmoplastic small round cell tumors) are primarily treated with systemic treatment in a multimodality setting. Metastasis surgery is established in isolated pulmonary metastases based on retrospective studies. This article focuses on recent development in treatment of adult type soft tissue sarcoma and GIST.

A phase II trial of weekly irinotecan in cisplatin-refractory esophageal cancer.

BACKGROUND: This study investigated the efficacy and toxicity of weekly single-agent irinotecan in patients with metastatic disease relapsing after cisplatin-based chemotherapy. PATIENTS AND METHODS: Fourteen patients were enrolled. A total number of 29 cycles (one cycle consisted of CPT-11 100 mg/m2 on days 1, 8, 15, qd 28) were applied. Irinotecan was continued until disease progression or unacceptable toxicity occurred. Where toxicity was less than WHO grade 3, the dose of irinotecan was escalated in 20 mg steps in subsequent cycles up to a maximum dose of 140 mg/m2. Patients were assessed for response according to WHO criteria every second cycle. RESULTS: Of the 13 evaluable patients, 2 achieved a partial response (PR) and 3 disease stabilisation (NC); progressive disease (PD) was noted in 8 patients. Median time to progression was 2 months (range: 1-8 months) and median survival from start of study treatment was 5 months (range: 2-16 months). Grade 3 toxicity consisted of diarrhea (n=3), fever (n=1) and pain (n=1). CONCLUSION: Single-agent irinotecan has moderate activity in cisplatin-refractory esophageal cancer.

Advances in the treatment of testicular cancer.

Testicular cancer is the most common solid tumour in young men, and the treatment of testicular germ cell tumours (TGCT) has been called a success story of medical oncology, germ cell cancer being regarded as the "model of a curable neoplasm". Even with metastatic disease, high cure rates can be achieved: the overall 5-year survival for all stages of TGCT is approximately 80%. Today, elaborate systems for prognostic evaluation for gonadal and extragonadal germ cell tumours facilitate the choice of the most appropriate therapy for individual patients. In doing so, the ultimate goal of treatment is tumour-free survival for any patient with TGCT. This goal has already been reached for >99% of the patients with early-stage tumours, as well as for the majority of patients with advanced disease (56% of patients with metastases are considered to have a good prognosis at the time of diagnosis; the 5-year survival rate for this group is 90%). However, patients with 'intermediate' or 'poor' prognosis at the time of diagnosis, as well as patients with relapsed disease after cisplatin-containing therapy, still have an unsatisfactorily low 5-year survival rate after standard therapy with PEB (cisplatin, etoposide, bleomycin) of only 80%, 45-55% and 20-25%, respectively.Therefore, our goals must be (i) to limit acute and chronic toxicity by avoiding overtreatment for patients with localised disease and/or good prognosis with advanced disease; and (ii) to identify patients with poor prognosis and treat them in specialised centres, where not only is optimal interdisciplinary care available but new treatment strategies are being applied. For example, tandem high-dose chemotherapy regimens might be effective in achieving higher cure rates in these patients.

Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma.

The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing's sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Most other high-grade (grading >I), so-called 'adult type', soft tissue sarcomas such as fibrosarcoma, liposarcoma, pleomorphic and synovial sarcomas are treated with an anthracycline-based regimen with or without ifosfamide as front-line therapy. In relapsed 'adult type' soft tissue sarcomas, trofosfamide, gemcitabine and trabectedin (ecteinascidin 743) appear to be drugs associated with some activity and an acceptable toxicity profile. A high activity has been reported for the taxanes, in particular for paclitaxel, in vascular sarcomas located in the scalp or face and in Kaposi's sarcoma. It is interesting to note that the different drugs have particular effects in distinct subtypes of soft tissue sarcoma; however, it should be taken into account that the number of patients included in the phase II trials is limited. The role of the newer agents (e.g. epothilones, brostallicin) is currently undefinable. Targeted therapy inhibiting vascular endothelial growth factor receptor, epidermal growth factor receptor, RAF kinase, c-KIT or platelet-derived growth factor receptors will continue to be tested in GIST patients refractory to imatinib and in other sarcoma histologies.

Toxicity of platinum compounds.

Since the introduction of platinum-based combination chemotherapy, particularly cisplatin, the outcome of the treatment of many solid tumours has changed. The leading platinum compounds in cancer chemotherapy are cisplatin, carboplatin and oxaliplatin. They share some structural similarities; however, there are marked differences between them in therapeutic use, pharmacokinetics and adverse effects profiles [1-4]. Compared to cisplatin, carboplatin has inferior efficacy in germ-cell tumour, head and neck cancer and bladder and oesophageal carcinoma, whereas both drugs seem to have comparable efficacy in advanced non-small cell and small cell lung cancer as well as ovarian cancer [5-7]. Oxaliplatin belongs to the group of diaminocyclohexane platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid [8,9]. Other platinum compounds such as oral JM216, ZD0473, BBR3464 and SPI-77, which is a pegylated liposomal formulation of cisplatin, are still under investigation [10-13], whereas nedaplatin has been approved in Japan for the treatment of non-small cell lung cancer and other solid tumours. This review focuses on cisplatin, carboplatin and oxaliplatin.

Mitomycin C and capecitabine in pretreated patients with metastatic gastric cancer: a multicenter phase II study.

PURPOSE: We conducted a multicenter phase II study to assess the toxicity and efficacy of a combination of mitomycin C (MMC) and capecitabine in pretreated patients with metastatic or locally advanced gastric cancer. METHODS: Thirty-nine patients (77 % male) between 33 and 78 years (median 66) with pretreated locally advanced or metastatic esophagogastric adenocarcinoma and eastern cooperative oncology group performance status of ≤2, measurable lesions, and adequate organ functions were recruited into the study. Eight patients (21 %) had received more than one prior chemotherapy regimen. Treatment consisted of three-weekly MMC 10 mg/m(2) day 1 and capecitabine 2,000 mg/m(2) (day 1-14; repeated day 22). RESULTS: A median of three cycles of therapy was administered. Grade 3 toxicity occurred in 20 patients (54 %). Main grade 3 adverse events were thrombocytopenia (11 %, n = 4), fatigue (8 %, n = 3), and neuropathy (8 %, n = 3). Two events of grade 4 toxicity were reported (5 %) (dyspnea and elevation of alkaline phosphatase due to bone metastases). Partial remission was noticed in 10.3 % (n = 4), stable disease in 33.3 % (n = 13) adding to a tumor control rate of 43.6 %. The median progression-free and overall survival were 2.8 and 5.6 months, respectively. CONCLUSION: The combination of MMC and capecitabine exhibited a favorable tolerability profile in pretreated patients with gastric cancer. The disease control rate compares adequately with that of other phase II and phase III trials for second-line therapy in gastric cancer. This regimen may be considered as an alternative second-line treatment, especially for patients not suitable for or pretreated with taxanes and/or irinotecan.