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Background: The PRODIGE-23 study showed a higher benefit for FOLFIRINOX (5-fluorouracil, irinotecan and oxaliplatin) as induction chemotherapy followed by long-course chemoradiotherapy (CTRT) respect to neoadjuvant CTRT alone both followed by total mesorectal excision (TME) in terms of disease-free survival (DFS) and overall survival (OS) in locally advanced rectal cancer (LARC). The added value of treatment intensification with irinotecan, over the doublet induction with fluoropyrimidine and oxaliplatin is still debated., Objective: To assess survival, pathological complete response (pCR) rate, and safety from phase II-III trials comparing triplet and doublet induction both followed by CTRT and TME in LARC., Methods: After a systematic literature review of PubMed, Embase, Cochrane, American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, data from Kaplan-Meier (KM) curves were extracted from phase II-III clinical trials. Phase II-III trials including at least one treatment arm with doublet or triplet induction chemotherapy without biological agents administered for a minimum of 3 months followed by long-course CTRT and TME and with at least 48 months of follow-up were selected. When available, the neoadjuvant CTRT alone arms of the selected studies were included as a comparator reference treatment. Individual patient DFS and OS data were extracted from Kaplan-Meier plots of original trials through graphical reconstruction between April 10th and May 19th, 2024. A pooled analysis was conducted, and results were validated in a subsequent network meta-analysis (NMA). pCR rates and grade ≥ 3 adverse events rates were also collected. Primary endpoints were DFS and OS between triplet and doublet induction. Secondary endpoints were DFS and OS between neoadjuvant CTRT alone and triplet or doublet induction as well as pCR rates and safety profile among different arms., Results: Out of 674 patients enrolled in 3 trials, 231, 161 and 282 were treated with FOLFIRINOX or CAPOX (capecitabine and oxaliplatin) followed by CTRT or neoadjuvant CTRT alone, respectively. 5-year DFS rates were 73.1 % [95 %CI: 67.2 % - 79.0 %], 61.7 % [95 %CI: 53.9 % - 69.5 %] and 65.1 % [95 %CI: 59.4 % - 70.8 %] for triplet induction, doublet induction, and neoadjuvant CTRT alone, respectively. 5-year OS rates were 86.8 % [95 %CI: 82.3 % - 91.3 %], 74.7 % [95 %CI: 67.6 % - 81.8 %], and 79.6 % [95 %CI: 74.9 % - 84.3 %] for FOLFIRINOX, CAPOX, and neoadjuvant CTRT alone, respectively. Triplet induction showed longer DFS and OS respect to doublet induction (HR for DFS: 0.67 [95 % CI 0.47 - 0.96], p = 0.03; HR for OS: 0.49 [95 % CI 0.31 - 0.78], p = 0.003) with a trend for superiority when compared with neoadjuvant CTRT alone (HR for DFS: 0.77 [95 % CI 0.57 - 1.05], p = 0.10; HR for OS: 0.67 [95 % CI 0.45 - 1.01], p = 0.06). No difference was observed between the doublet induction and neoadjuvant CTRT groups. pCR rates were higher for patients treated with FOLFIRINOX (27.7 %) respect to subjects receiving CAPOX (19.7 %, p = 0.02) or neoadjuvant CTRT alone (12.5 %, p < 0.0001). Triplet was associated with higher rates of severe neutropenia (17 % vs 1 %, p < 0.0001) and nausea-vomiting (11 % vs 3 %, p = 0.02) respect to doublet induction., Conclusions: Induction with FOLFIRINOX showed better survival outcomes and pCR rates respect to CAPOX at the price of increased G3-4 neutropenia and nausea/vomiting. A randomized study comparing triplet and doublet chemotherapy in the frame of a total neoadjuvant treatment strategy is widely warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. C.C. has received honoraria for speaker or advisory roles from Bayer, Roche, Merck Serono, Amgen, Servier, Mirati, Pierre Fabre, MSD, Nordic Pharma and Takeda; and research grants from Bayer, Servier, Merck and Amgen.G.M. has received payment or honoraria for lectures, presentations, speakers bureaux, manuscript writing or educational events from Roche, MSD, Eisai, Terumo, Amgen, Merck Serono; support for attending meetings and or travel from Roche, MSD, Eisai, Terumo, Amgen, Merck Serono; participation on a Data Safety Monitoring Board or Advisory Board from Roche,MSD, Eisai.R.M., G.V., M.C., P.C. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases. The recent approval of the three drugs brentuximab vedotin (BV), pralatrexate, and belinostat for patients with relapsed or refractory disease has provided clues about pathophysiology and future directions, though challenges satisfying post-marketing requirements (PMR) for those accelerated approvals have led to one of those drugs being withdrawn and put the other two in jeopardy. Edits of the front-line regimens, often called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-plus approaches, look more like CHOP-minus strategies, as the toxicity of five-drug regimens often reduces the dose intensity of the added 'novel' drug, nullifying any hope of an advance. The turmoil in the field produced by the aforementioned, coupled with an ever-changing classification, has left the field uncertain about the path forward. Despite these challenges, empiric findings from studies of novel drug approaches, coupled with a logic emerging from studies of PTCL lymphomagenesis, have begun to illuminate, albeit faintly for some, a potential direction. The empiric finding that drugs targeting the discrete components of the PTCL epigenome, coupled with the description of multiple mutations in genes that govern epigenetic biology, offers, at the very least, an opportunity to finally be hypothesis-driven. The most recent recognition that the only combination of drugs shown to markedly improve progression-free survival (PFS) in patients with relapsed disease is one based on dual targeting of different and discrete components of that epigenetic biology has established a possibility that circumnavigating chemotherapy addition studies is both plausible, feasible, and likely the best prospect for a quantum advance in this disease. Herein, we analyze PTCL through a 2025 lens, highlighting and underscoring walls that have impeded progress. We will critically explore all the clues and the panoramic view of PTCL research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metronomic chemotherapy (M-CT) is defined as dose dense administration of chemotherapy at lower doses than maximum tolerated dose but at shorter free intervals, to obtain a near continuous exposure of cancer cells to those potentially effective drugs. M-CT is a useful strategy to obtain response, overcome resistance and reduce side effects, with low costs. This review will focus on the use of M-CT in advanced breast cancer (ABC). Cytostatic and cytotoxic effect on cancer cells, the anti-angiogenic and the immunomodulatory effects are its main mechanisms of actions. Many clinical trials proved the efficacy and tolerability of different monotherapies and combinations of chemotherapeutic agents administered in metronomic doses and frequencies in ABC. M-CT is a reasonable option for second and later lines of chemotherapy in metastatic breast cancer including those with prior anthracycline or taxane exposure, older patients and patients with comorbidities, and even as first-line in certain groups of patients. The acceptable efficacy and low toxicity of oral metronomic chemotherapy makes it a reasonable option during COVID-19 pandemic as well as in the post-COVID era which is projected to last for some time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC., Methods: We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models., Results: Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8 + infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion., Conclusions: Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. E. Nadal has received honoraria for participating in advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim and AstraZeneca. E. Nadal has received research funding from Roche and Pfizer.J. Bosch-Barrera serves on advisory boards and/or accepted honoraria for giving lectures from Bristol Myers-Squibb (BMS), Roche, Merck Sharp & Dohme (MSD), AstraZeneca, Novartis and Boehringer-Ingelheim. J. Bosch-Barrera has also received grants for research from Pfizer and Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Our understanding of the complex, adaptive mechanisms of response to targeted therapies in metastatic melanoma is now leading to more effective combination treatments. These include the simultaneous inhibition of signalling pathways and metabolic programmes, as well as epigenetic mechanisms or immunological checkpoints. We review the latest pre-clinical and clinical results of strategies to delay tumor progression through combination approaches, and also highlight some of the problems ahead, including patient stratification, the complexity of targeting adaptive responses, and the management of more severe toxicities that result from double and triple-drug treatments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60-70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies. Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community. This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer., Materials and Methods: A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included., Results: This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described., Conclusion: Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Chemotherapy for men with metastatic castration-resistant prostate cancer (CRPC) conferred no survival advantage until 2004 when docetaxel was shown to improve survival when compared with mitoxantrone, which was approved for palliation of symptomatic disease in 1996. Since then, clinical trials have concentrated on three main populations of patients with metastatic CRPC: those who are chemotherapy naïve and are asymptomatic or minimally symptomatic, those who need docetaxel therapy, and those who have received docetaxel previously and/or those with symptomatic disease. Over the last year, four Phase III therapeutic trials have met their primary endpoint of improved overall survival: sipuleucel-T in the pre-chemotherapy setting, cabazitaxel and abiraterone in the post-docetaxel setting, and radium-223 for those with symptomatic bone metastases who have received or are not suitable to receive docetaxel. In addition to these therapeutic trials, a Phase III head-to-head trial of denosumab compared to zoledronic acid showed that denosumab was superior to zoledronic acid in delaying or preventing skeletal related events. As a result, the treatment paradigm for metastatic CRPC is changing rapidly. This paper reviews the data from these five completed Phase III trials and places these new agents, as well as those in ongoing Phase III trials, in the context of the old treatment paradigm for metastatic CRPC and discusses some of the challenges ahead for determining optimal timing and sequencing of treatments for metastatic CRPC., (Copyright © 2011. Published by Elsevier Ltd.)

Lapatinib, an orally available dual inhibitor targeting the tyrosine-kinase domain of both epidermal growth factor receptor-1 and 2, has been introduced for the treatment of advanced/metastatic HER2+ breast cancer in combination with capacitabine after chemotherapy regimens containing anthracycline, taxanes and trastuzumab. Moreover, lapatinib is under investigation in combination with anthracycline and taxanes in neoadjuvant and adjuvant settings. Another potential field of investigation for this drug is related to its ability to restore hormonal sensitivity of HER2-, hormone-receptor positive breast cancer cells. This paper reviews the current use of lapatinib in breast cancer and its future perspectives., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Whereas first-line chemotherapy (CT) with single-agent gemcitabine or gemcitabine-based combinations provides a proven benefit in patients with locally advanced or metastatic pancreatic cancer (PC), the role of salvage CT after gemcitabine-failure is not well-established and to date no regimen has emerged as preferred in this setting. Several clinical trials have investigated the efficacy and toxicity-profile of second-line CT and indicated that selected patients may obtain significant benefit from it, also with regard to survival. However, definitive results from large randomized phase III studies are still lacking, and the evidence for clinical benefit of salvage CT is based on small phase II trials that evaluated different treatment schedules in heterogeneous populations. The main goal of this paper is reviewing this topic.

The liver is a common site of metastases in breast cancer. Although the development of liver metastases has long been associated with a poor prognosis in this disease, this dogma has been challenged by more recent data, perhaps reflecting some treatment and other technological advances achieved in the last decade. Nevertheless, the specific population of breast cancer patients presenting with liver disease and associated liver dysfunction remain poorly studied. These women still seem to have a poor prognosis as compared to other patients with liver metastases. This is further complicated by the fact that the most active cytotoxic agents in breast cancer have significant hepatic metabolism and/or biliary excretion. Unfortunately, since these patients have been most of the time excluded from clinical trials, there are currently no clear recommendations for the management of such dramatic presentations. With some exceptions, recommendations for dose adjustments have also been largely empirical. In this paper, we review the optimal doses of cytotoxics used in this clinical situation and provide some tips on the management of these patients, based on the limited data currently available in the literature.

Patients with colorectal cancer commonly succumb to the sequelae of hepatic metastases. Response to systemic therapy is inadequate. Hepatic arterial infusion (HAI) exposes liver metastases to high local concentrations of drug. Herein, we review the randomized trials of HAI in colorectal cancer. Data for this review were identified by searches of MEDLINE and references from relevant articles using the search terms "infusion intra-arterial" and "colorectal cancer." Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English between 1966 and 2003 were included. Randomized trials (5-fluorouracil- (5-FU-) or fluordeoxyuridine- (FUDR-) based regimens) often demonstrated superior response rates for HAI as compared to systemic chemotherapy (primary treatment or post-resection). Enhanced survival has, however, shown only when HAI was combined with systemic chemotherapy in the post-resection setting. For 5-FU-based and perhaps other regimens, randomized trials of combined regional and systemic therapy versus systemic treatment alone may be needed in order to determine whether or not there is a survival advantage after HAI in unresectable patients, as has been recently demonstrated in resectable patients. A variety of agents other than 5-FU have also been given by HAI to patients with liver metastases from diverse cancers. Such regional therapy often yields encouraging response rates and impact on survival therefore merits investigation.

At diagnosis, 25-40% of patients with small cell lung cancer (SCLC) are 70 years of age or older, and many of them have been undertreated because of fear of excessive toxicity associated with chemotherapy. Papers retrieved by a Medline search using the key words "elderly or older" and "small cell lung cancer" and by a manual search were classified into the three types: (1) case-series studies, (2) subgroup analyses of phase II and phase III trials by age, and (3) prospective clinical trials in the elderly. Treatment regimens, delivery, toxicity, antitumor activity, and patient survival were reviewed in elderly patients with good and poor general condition. The standard chemotherapy regimens for the general population could be applied to elderly patients in good general condition (performance status of 0-1, normal organ function, and no comorbidity), but etoposide and carboplatin regimen with dose modification was frequently used for unselected elderly patients. A combination of full-dose thoracic radiotherapy and chemotherapy was the treatment of choice for limited SCLC in the elderly. Full cycles of chemotherapy were tolerable by 80% of the elderly patients with good general condition, but two cycles may be optimal for unselected elderly patients. Although the evidence levels based on clinical trials available today are low, these results are helpful for clinical practice and future clinical trials for elderly patients with SCLC.

The diagnosis of cancer in men or women leads to prompt evaluation of the extent of the cancer, its treatment, and subsequent prognosis. However, relatively little emphasis is placed on fertility following the completion of therapy. As the effectiveness of cancer treatment has improved, men can enjoy a longer life that is free of cancer. However, chemotherapeutic regimens alone or in combination with radiation therapy frequently result in azoospermia or infertility. This paper reviews available methods to maintain male fertility in patients undergoing chemotherapy or radiation therapy. Certain chemotherapeutic agents that are less likely to cause azoospermia may be incorporated into potentially curative therapies. Hormonal suppression applied early (prior to) and during chemotherapy may protect future male fertility. Alternatively, cryopreservation of sperm enables men to reproduce in the future with the assistance of in vitro fertilization with intracytoplasmic sperm injection. Therefore, oncologists need to discuss male fertility preservation before initiating cancer treatment in reproductive-aged men. The emphasis for future cancer treatment and its research regarding male fertility preservation needs further attention.

The interactions of cisplatin with other anti-cancer agents on the DNA level have been studied extensively in pre-clinical experiments. In general, combination of cisplatin with an antimetabolite, taxane, or topoisomerase inhibitor, can result in a modulation of platinum pharmacology on the DNA, for example, enhanced retention of the platinum-DNA adducts. These interactions are mostly sequence and cell type dependent. In cell line models, antimetabolites can enhance the number of platinum-DNA adducts, probably by inhibition of DNA repair pathways. However, in clinical trials, the opposite effect has been observed, with a reduction of these adducts upon combined treatment. For the taxanes it has been shown that they can inhibit the formation of platinum-DNA adducts, whereas topoisomerase I inhibitors increase the number of adducts, resulting in strong synergistic cytotoxicity. For this last interaction a mechanistic model has recently been proposed, in which the topoisomerase I enzyme directly binds to the platinum-DNA adduct. Thereafter, the topoisomerase I inhibitor binds to this complex, which yields large stabilised lesions to the DNA that are probably difficult to repair. Ongoing studies will proceed to elucidate the exact mechanism underlying the interactions between cisplatin and other anti-neoplastic agents on the DNA level. Such increased understanding might help in designing new and more effective treatment regimens for cancer. In this paper, we review the pre-clinical and clinical studies investigating the observed interactions between cisplatin, the antimetabolites, taxanes, and topoisomerase inhibitors on the DNA level.

Recent advances in understanding how response or resistance to cytotoxic drugs develops at the cellular level resulted in the development of novel, non-cytotoxic agents that modulate response the chemotherapy. 'Chemo-signal therapy', the combination of chemotherapy with cellular response modifiers, is a very promising new treatment modality that has entered the arena of clinical trials. Clinical experience with the anti-HER-2 antibody, trastuzumab, in breast cancer has demonstrated that manipulation of growth factor signalling can enhance sensitivity to cytotoxic drugs in a clinically meaningful way. Several other agents that were designed to modulate response to chemotherapy are currently in early phases of clinical drug development. It is likely that some of these new molecules will have a major impact on how chemotherapy will be given in the next decade. This paper will review current clinical research with a select group of chemotherapy response modifiers. We will focus on agents that modulate signal transduction, oncogene expression and apoptosis with an emphasis on breast cancer., (Copyright 1999 Harcourt Publishers Ltd.)