Current pharmacotherapy for testicular germ cell cancer

Introduction: With the implementation of platinum-based chemotherapy, germ cell tumors (GCTs) became a model for a curable solid tumor, with survival rates of 95% in all patients with >80% survival in metastatic stages.

Areas covered: Herein, the authors review the current standards of adjuvant chemotherapy for stage I GCTs as well as first-line and salvage treatments for metastatic disease. Novel approaches for refractory disease are also reviewed.

Expert opinion: Active surveillance should be considered for all stage I patients and is the preferred approach for stage I seminoma. In stage I non-seminomas with vascular invasion, one cycle of bleomycin, etoposide, and cisplatin (BEP) substantially reduces the relapse risk. For most advanced GCTs, BEP remains the first-line standard of care. For poor prognosis disease treatment, stratification according to tumor marker decline is recommended. The role of primary high-dose chemotherapy (HDCT) for selected very high-risk patients remains to be prospectively evaluated. Salvage HDCT at relapse seems superior to conventional chemotherapy, retrospectively. The treatment of multiply relapsed disease remains challenging. The gemcitabine/oxaliplatin/paclitaxel (GOP) protocol is considered the standard for refractory disease. However, overall, outcomes are poor and new treatment approaches are urgently needed with targeted therapies so far failing to yield relevant clinical activity.     

Treatment options for esophageal squamous cell carcinoma

Introduction: The treatment for esophageal squamous cell carcinoma (SCC) depends on its etiology. For mucosal cancer, endoscopic resection is standard; while for locally advanced cancer, esophagectomy is the main treatment. When the tumor is more advanced, neoadjuvant or adjuvant therapy is added. For unresectable cancer, concurrent chemoradiotherapy is the standard therapy.

Areas covered: The standard chemotherapy for esophageal SCC is a cisplatin- and 5-fluorouracil (CF)-based regimen. Chemoradiotherapy (CRT) is the standard treatment for unresectable esophageal SCC and is also an option for resectable tumors. For patients who are inoperable, concurrent CRT should be the standard of care. Docetaxel, cisplatin and 5-fluorouracil (DCF) therapy is a promising candidate for chemotherapy with or without radiotherapy because an excellent local control rate and pathological remission rate have been reported. Although salvage surgery after definitive CRT is a practical treatment, judicious patient selection is crucial.

Expert opinion: Presently, the standard regimen for esophageal SCC is CF. DCF is expected to be the next standard regimen. In the near future, some new therapeutic options, such as molecular targeted therapy or particle beam therapy, may confer further advantages. A thorough understanding of these therapeutic modalities is important to achieve this endeavor.     

Pharmacotherapy of relapsed metastatic testicular cancer

Background: Patients with metastatic testicular cancer exhibit an excellent prognosis. However, the outcome for patients with relapse after cisplatin-based chemotherapy remains unsatisfactory. Several larger studies have been recently published. Objective: To review the treatment of patients with testicular cancer after failure of first-line chemotherapy. Methods: A literature search was performed for studies investigating therapies for relapsed testicular cancer. Results/conclusions: The prognosis of patients relapsing after first-line cisplatin-based chemotherapy has improved with multimodality therapy, including conventional and high-dose chemotherapy, surgery and radiation. Prognostic factors are increasingly used to guide treatment intensity. High-dose chemotherapy has become an accepted treatment option, in particular in patients with poor risk factors at relapse. The outcome of patients with multiply relapsed or cisplatin-refractory disease remains particularly poor. Treatment of relapsed patients requires a close cooperation of medical oncologists, urologists, surgeons and radiation oncologists with extensive experience in this disease.     

Clinical outcome of high-dose chemotherapy combined with peripheral blood stem cell transplantation for male germ cell tumors

Peripheral blood stem cell transplantation (PBSCT) is widely performed currently instead of bone marrow transplantation (BMT) because bone marrow reconstruction is better and the procedure is less invasive. We applied 26 courses of high-dose chemotherapy (1250 mg/m2 of carboplatin, 1500 mg/m2 of etoposide and 7.5 g/m2 of ifosfamide) to 14 male patients with germ cell tumors. Eleven patients underwent high-dose chemotherapy as induction after two to three courses of conventional BEP therapy. The remaining three patients had recurrent disease after conventional chemotherapies. Peripheral blood stem cells were harvested during previous chemotherapy and sufficient CD34+ cells were harvested for transplantation. Although all patients had grade 4 hematotoxicity, the white blood cell count recovered to more than 1000/microl within 8-11 days after PBSCT. No treatment-related death was found. Nine of 14 patients (64.3%) remain disease free at 18 months of median follow up time (range 12-60). We conclude that high-dose chemotherapy is a safe and effective means of treating advanced or refractory germ cell tumors in male patients.     

Pharmacotherapy of gestational trophoblastic disease

Gestational trophoblastic neoplasms are the most responsive of all solid tumours to chemotherapy leading to an overall cure rate of > 90%. Nonmetastatic disease (FIGO Stage I) and low-risk metastatic disease (FIGO Stages II and III; WHO score < 7) can be treated with single-agent methotrexate or actinomycin D protocols resulting in a survival rate approaching 100%. Metastatic high-risk disease (FIGO Stage IV or WHO score > 7) should be treated with initial intensive multimodality therapy with combination chemotherapy, consisting of etoposide, high-dose methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) and adjuvant radiotherapy and surgery when indicated. Despite this aggressive approach, ～ 30% of patients with high-risk disease will fail initial therapy or relapse from remission. Salvage chemotherapy with drug regimens containing platinum agents and etoposide, usually in conjunction with bleomycin or ifosfamide, as well as surgical resection of sites of resistant disease, will ultimately result in a survival rate of 80 – 90% for metastatic high-risk disease.     

Adjuvant medical therapy for prostate cancer

Importance of the field: Prostate cancer is a common cancer and the role of adjuvant medical therapy continues to be investigated. An understanding of the use of adjuvant medical therapy is essential for the appropriate care of prostate cancer patients, especially for those with locally advanced or high-risk disease.

Areas covered in this review: This article reviews the role of adjuvant treatment of non-metastatic prostate cancer. To identify all pertinent publications, a literature search of the National Library of Medicine (PubMed) from inception to 22 June 2010 was conducted for ‘adjuvant prostate cancer’, with these results filtered for clinical trials and systematic reviews.

What the reader will gain: This work reviews the uses of adjuvant androgen deprivation therapy and chemotherapy for prostate cancer. There is a clear benefit from the use of androgen deprivation therapy in conjunction with radiation therapy for selected patients, but the role of postoperative chemotherapy is poorly defined. Identifying appropriate patients for adjuvant therapy continues to be a challenge.

Take home message: There is a complex literature describing the role of adjuvant medical therapy in prostate cancer, which is reviewed here. Continuing and future clinical trials will define the utility of adjuvant therapy in this setting and require the support of the clinical community.     

Feasibility and usefulness of high-dose chemotherapy (high-dose ifosfamide, carboplatin and etoposide) combined with peripheral blood stem cell transplantation for male germ cell tumor: a single-institute experience

Although the usefulness of high-dose chemotherapy with peripheral blood stem cell transplantation for advanced germ cell tumor is still under evaluation in phase III randomized controlled studies, this approach is currently used as one treatment option for relapsed or advanced male germ cell tumor. Clinical outcomes of high-dose chemotherapy for a single institute from Japan are presented herein. We administered 63 courses of high-dose ifosfamide, carboplatin and etoposide chemotherapy (1250 mg/m carboplatin; 1500 mg/m etoposide; 7.5 g/m ifosfamide) to 34 men with germ cell tumors. Of these, 27 patients underwent high-dose ifosfamide, carboplatin and etoposide as first-line therapy after 2-3 courses of conventional bleomycin, etoposide and cisplatin chemotherapy, and seven patients underwent high-dose ifosfamide, carboplatin and etoposide for relapsed germ cell tumor. Peripheral blood stem cells were harvested during previous chemotherapy and sufficient CD34 cells were harvested for transplantation. Although all patients experienced grade 4 hemotoxicity, leukocyte counts recovered to above 1000/mul within 8-11 days after peripheral blood stem cell transplantation. No treatment-related deaths occurred. After a mean follow-up of 45 months (range 12-118 months), 23 of 34 patients (67.6%) remained disease-free. High-dose ifosfamide, carboplatin and etoposide could be performed safely, and could offer an effective means of treating advanced or refractory germ cell tumors in men.     

Drug design strategies for the treatment of prostate cancer

Introduction: While metastatic prostate cancer remains an incurable tumor, remarkable progress has been made with novel drug design strategies for this incurable disease. Several new agents, including hormonal analogues, cytotoxic chemotherapy drugs, radionuclides and innovative targeted therapies, have recently been approved by the FDA for use in advanced and/or metastatic castrate-resistant prostate cancer. Furthermore, a growing number of new diagnostic or predictive genetic tests have also been incorporated into the management of this disease. Immunotherapy-based approaches have shown promise and have led to drug approvals. Other experimental approaches such as vascular targeting are in early translational clinical trials.

Areas covered: Herein, the authors outline select state-of-the-art approaches in the field. They also discuss the current challenges and future opportunities in the medical care of prostate cancer patients.

Expert opinion: An inherent challenge in the treatment of prostate cancer is to determine which patients need immediate aggressive treatment versus active surveillance. For patients needing aggressive treatment, integrating the sequence of therapeutic interventions, to provide the most benefit, remains a challenge that clinicians face. Recently, several genetic tests have been approved, facilitating early treatment decisions. Innovative targeted therapies are moving towards clinical applications, providing treatment options for tumors previously considered refractory to androgen ablation treatment.     

Advances in pharmacotherapy of small cell lung cancer

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastatic dissemination and responsiveness to initial therapy. The incidence of SCLC has been declining over the past two decades. Limited-stage SCLC is a potentially curable disease with long-term survival of ～ 20% when treated with platinum-based chemotherapy plus concurrent thoracic radiation and prophylactic cranial irradiation. For patients with extensive-stage SCLC, survival can be increased with combination platinum-based chemotherapy, but the disease remains incurable.

Areas covered: This review looks at the current advances in pharmacotherapy for SCLC.

Expert opinion: Many chemotherapeutic strategies and newer cytotoxic agents have been evaluated in SCLC, and some had promising activity in early clinical trials. However, none have demonstrated consistent improvements in outcome over standard platinum-based treatment. Similarly, although many potential molecular targets have been identified in preclinical studies of SCLC, molecularly targeted therapy has yet to demonstrate any substantial activity in clinical trials. Nonetheless, future advances in this disease will undoubtedly depend on improvements in our understanding of the molecular mechanisms that drive the proliferation and survival of SCLC cells.     

Diagnosis and treatment of patients with testicular germ cell cancer.

Testicular germ cell tumours are a highly curable malignancy even in the presence of metastases, with an overall survival rate of approximately 90 to 95% when all stages are considered. Current therapeutic strategies aim at risk-adapted therapy, trying to maintain favourable overall results while reducing treatment-related toxicity, particularly in non-advanced disease. In stage I disease, unilateral inguinal orchiectomy represents the standard diagnostic and therapeutic approach. For patients with clinical stage I seminoma, prophylactic para-aortic radiotherapy with 26Gy is commonly employed. In patients with nonseminomatous germ cell tumours (NSGCT) at clinical stage I, the 3 options are: (i) retroperitoneal lymphadenectomy; (ii) a wait-and-see strategy; or (iii) 2 cycles of adjuvant chemotherapy. The individual risk profile for tumour recurrence, mainly based on histopathological criteria such as vascular tumour invasion, should guide treatment decisions in this group of patients. Radiotherapy is still the standard approach in clinical stage IIA/B seminoma, whereas in patients with a low tumour burden of NSGCT, retroperitoneal lymphadenectomy is frequently used followed by surveillance or adjuvant chemotherapy. Primary chemotherapy in these stages of disease may be at least equally successful. Major progress has also been achieved in the treatment of NSGCT patients with metastatic disease greater than clinical stage IIB, for whom primary chemotherapy represents the standard approach. After cisplatin-based combination chemotherapy, between 70 and 90% of patients will achieve a durable remission. In patients with 'good risk' metastatic disease, 3 cycles of cisplatin, etoposide and bleomycin (PEB) remain the standard treatment, despite several randomised trials trying to avoid the lung-toxic bleomycin or substituting cisplatin by carboplatin. In patients with 'intermediate' and 'poor prognosis' disease, 4 cycles of PEB given at 3-week intervals are considered routine treatment. The role of high dose chemotherapy with peripheral autologous blood stem cell transplantation is currently being investigated for patients presenting initially with advanced (poor prognosis) metastatic disease and for patients with relapse after previous chemotherapy, in whom conventional-dose salvage regimens will only result in 20% long-term survival. Because of the large group of patients with metastatic disease being cured, the possible long-term adverse effects of treatment have become important. Only a slightly elevated risk for therapy-related secondary malignancies has been identified. Long-term adverse effects associated with cisplatin may affect a larger proportion of patients. Further research should focus on reducing the risk of chemotherapy-related chronic toxicity.     

Phase II study of bendamustine in patients with relapsed or cisplatin-refractory germ cell cancer

Despite generally high cure rates in patients with metastatic germ cell cancer, patients with incomplete response to first-line cisplatin-based chemotherapy or with relapsed disease following high-dose salvage therapy exhibit a very poor prognosis. We investigated the efficacy and toxicity of bendamustine, a bifunctional alkylating benzimidol derivative with only partial cross-resistance to other alkylating agents such as ifosfamide or cyclophosphamide. Nineteen patients with cisplatin-refractory germ cell tumors (GCT) or relapse after high-dose chemotherapy plus autologous stem cell support were treated with bendamustine at a dose of 120 mg/m2 on 2 consecutive days at 3 week intervals. Patients had received a median of 9 (range 4-20) platinum-containing treatment cycles prior to bendamustine and 13 patients (68%) had previously received carboplatin/etoposide-based high-dose chemotherapy. One patient achieved a partial remission of only 6 weeks duration. No other responses were seen. Toxicity was low with one patient developing WHO grade 3 thrombocytopenia as the only WHO grade 3/4 toxicity observed. Hematologic toxicity was similar in patients pretreated with and without high-dose chemotherapy plus autologous stem cell support. We conclude that bendamustine has little or no clinically relevant activity in patients with cisplatin-refractory GCT or relapsed disease after high-dose chemotherapy.     

Systemic therapy for the treatment of endometrial cancer

ABSTRACT

Introduction: Endometrial cancer (EC) is one of the most frequent gynecological cancers worldwide. The gold standard treatment of EC is most certainly surgery and may very well be the only therapy in the early stages of disease. To improve outcomes in non-early EC, adjuvant therapy is often employed but this is not standardized. Adjuvant options can include radiotherapy, chemotherapy or a combination of both. Adjuvant chemotherapy could be indicated in high-risk stage I and II or advanced stage EC. Several clinical trials are ongoing in an attempt to define the optimal adjuvant treatment. Furthermore, chemotherapy is the front-line therapy in advanced unresectable, metastatic or recurrent endometrial cancer.

Areas covered: Herein, the authors review the first-line chemotherapy for the treatment of endometrial cancer and provide their expert perspectives on these therapies.

Expert opinion: Chemotherapy is fundamental in advanced/recurrent EC. Further evidence is needed to characterize the role of adjuvant chemotherapy. Future studies should consider genomic and molecular heterogeneities to identify even more efficient tailored therapies.     

Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update

Introduction: Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life.

Areas covered: Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC.

Expert opinion: Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated.     

Pharmacotherapy of Hodgkin lymphoma: standard approaches and future perspectives

Introduction: Hodgkin lymphoma (HL) is a lymphoid malignancy with an incidence of 2 – 3/100,000/year. Young adults are most often affected. Due to the development of highly active multi-agent chemotherapy protocols and the optimization of radiotherapy (RT) fields and doses, HL has become one of the malignancies with the highest cure rates. As treatment efficacy can hardly be improved, the major goal of clinical HL research consists in decreasing therapy-associated acute and long-term toxicity. To this end, treatment stratification based on interim positron emission tomography and the implementation of targeted drugs such as the antibody-drug conjugate brentuximab vedotin are currently being evaluated in prospective trials.

Areas covered: This article reviews recent randomized Phase III and larger Phase II trials including HL patients.

Expert opinion: In early stage HL, excellent results are achieved with a brief chemotherapy followed by involved-field RT. Patients with advanced HL should receive six to eight cycles of chemotherapy optionally followed by localized RT. In relapsed disease, high-dose chemotherapy followed by autologous stem cell transplantation represents the standard of care for most patients. The use of novel drugs and imaging tools that currently undergo evaluation may optimize HL treatment.     

Pharmacotherapy of head and neck cancer

Introduction: There are over 55,000 new cases of head and neck cancer diagnosed annually in the United States. Historically surgical resection was the standard of care, but due to vital structures in the head and neck region this led to severe morbidity. The integration of pharmacotherapy has rapidly expanded over the years into a multimodality treatment paradigm for locally advanced head and neck cancer, allowing organ-sparing treatment approaches. Here we discuss the various approaches and settings in which chemotherapy can be incorporated into the management of head and neck squamous cell carcinoma (HNSCC).

Areas covered: Chemotherapy in HNSCC can be administered in several different treatment circumstances: in the metastatic setting for palliation of symptoms and prolongation of survival, before definitive local treatment (induction), as part of definitive treatment simultaneously with radiation (concurrent) or after definitive local therapy (adjuvant).

Expert opinion: The incorporation of chemotherapy into the management of patients with head and neck cancer has allowed organ preservation approaches and improved survival. Because of the toxicities of chemotherapy, it is imperative that chemotherapy is only administered to the appropriate patient population who are more likely to benefit. Cisplatin 100 mg/m² given in combination with radiation in the non-metastatic setting is the most widely tested regimen and remains the reference regimen. Cetuximab is also an alternative, but there is no data to support the use of cetuximab in a laryngeal preservation approach or in the postoperative setting.     

Pharmacotherapy of cervical cancer

Importance of the field: Cervical cancer (CC) remains an important health problem. It is the second most frequent malignancy in women worldwide, with one-third of patients dying from pharmacoresistant disease.

Areas covered in this review: We reviewed pharmacotherapy approaches in the medical and multidisciplinary management of CC and conducted a systematic search of Pubmed for clinical trials, reviews and meta-analysis published in the last 20 years. Abstracts of the American Society of Clinical Oncology, European Society of Gynecological Oncology and International Gynecologic Cancer Society were also searched, together with the US National Institutes of Health clinical trial database.

What the reader will gain: The state-of-the art of cytotoxic and biologically targeted therapies in early, locally advanced and metastatic/recurrent CC is discussed.

Take home message: Until recently, the role of pharmacotherapy in CC was restricted to palliation of advanced/metastatic or recurrent disease. During the past two decades, this reluctant attitude towards chemotherapy has been modified after a series of randomized trials demonstrated its beneficial contribution as an adjunct to radiotherapy or surgery in early and locally advanced CC. Moreover, new combinations of cytotoxics, together with novel molecular target agents, open new perspectives in the treatment of primary and recurrent CC.     

Evolving pharmacotherapeutic strategies for small bowel adenocarcinoma

Importance of the field: Owing to nonspecific signs and symptoms, the majority of patients with small bowel adenocarcinoma (SBA) present with advanced-stage disease. Few studies in the literature adequately address the role of chemotherapy in SBA. The regimens used in colon and gastric cancers have been tried in SBA with varying degrees of success.

Areas covered in this review: The authors explore the natural history and diagnostic evaluation of SBA, followed by a focused review of existing studies on individual agents and combinations used in the therapy of this malignancy.

What the reader will gain: 5-fluorouracil-based chemotherapy seems to offer a clinical benefit in advanced SBA. The reader will acquire considerable insights about the most effective chemotherapy drugs and combination regimens used in advanced SBA.

Take home message: Given the rarity of this malignancy, multicenter, randomized clinical trials are essential in the design of optimal therapeutic strategies for SBA. The role of adjuvant therapy in SBA remains to be clarified. Prospective evaluation of new agents and their incorporation into various therapeutic schemes for advanced/metastatic disease is also necessary. Until then, therapeutic decisions should be individualized and based on the benefits and toxicities of the most effective drugs or combinations.     

Response of metastatic adenoid cystic carcinoma and Merkel cell tumor to high-dose Melphalan with autologous bone marrow transplantation

Summary Two patients with metastatic spread of unusual tumors responded to treatment with high-dose Melphalan and autologous bone marrow transplant. One patient had adenoid cystic carcinoma of a minor salivary gland and the other had Merkel cell tumor of the scalp. Both patients had undergone prior surgery and radiotherapy, but later relapsed with distant metastases. Both patients had progression of their disease despite conventional and salvage chemotherapy. Treatment with high-dose Melphalan and autologous bone marrow transplant resulted in partial responses for both patients. High-dose Melphalan should be considered for therapy earlier in the course of patients with these unusual cancers.     

The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials

Introduction: An increasing number of basic, translational and clinical studies demonstrate the importance of the protein tyrosine kinase receptor, c-Met, in the progression of prostate cancer. c-Met is overexpressed in primary prostate cancers, further increased in expression in bone metastases and is associated with the development of castrate-resistant disease. Because of its importance as a target, c-Met inhibitors have reached clinical trial for advanced, castrate-resistant prostate cancer.

Areas covered: In this review, altered expression of c-Met and hepatocyte growth factor in prostate tumors and the microenvironment and how they contribute to growth and invasion of prostate cancer cells is described. Next, preclinical studies providing the support for use of c-Met inhibitors are discussed. Finally, early promising results from c-Met inhibitors in clinical trial, and future prospects for c-Met inhibitors in the treatment of advanced stage prostate cancer, are discussed.

Expert opinion: An emerging theme in treating metastatic prostate cancer is the requirement to target both the epithelial and stromal compartments. Results from clinical trials suggest that inhibitors of c-Met that block stromal-mediated c-Met activation in prostate tumors may be important therapeutic agents in at least a subset of patients with metastatic prostate cancer. However, as many of the inhibitors have multiple targets, the efficacy of targeting c-Met alone remains to be determined.