Ibrutinib combinations in CLL therapy: scientific rationale and clinical results

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.Subject terms: Combination drug therapy, Medical research     

Noninvasive screening tests for metastatic melanoma: rationale and results

When melanoma metastasizes to distant organs, the most common sites of involvement are lung, liver, bone and brain. In addition to conventional x-ray and radioisotopic studies, ultrasonography and computed tomography are being utilized in increasing frequency. The yield and reliability of these noninvasive tests among patients with various stages of melanoma are presented. Other than chest x-rays, the routine use of such tests to screen patients with early melanoma for occult lesions of the liver, bone and brain is not indicated. Even among patients with advanced melanomas, such tests should be used for staging purpose only in patients with symptoms or specific indications.     

Enhancing the clinical activity of sorafenib through dose escalation: rationale and current experience

Sorafenib is an oral multitargeted tyrosine and serine/threonine kinase inhibitor approved for the treatment of advanced renal cell and hepatocellular carcinoma. An understanding of its dose-toxicity relationship has paved the way for trials seeking to enhance its clinical activity through the exploration of alternative dosing strategies. In this article, we review the dose-toxicity relationship of sorafenib observed during its phase I and early phase II testing, explore its toxicity profile at the recommended dose and schedule, discuss the evidence for dose escalation to higher levels, and examine the preliminary evidence for clinical activity of this strategy. Owing to a temporal relationship between toxicity and dose, it may be possible in select patients to escalate sorafenib to doses beyond those currently employed. However, because of the potential for increased toxicity, sorafenib dose escalation should currently be performed only in the context of a clinical trial.     

Radiation therapy and sorafenib: clinical data and rationale for the combination in metastatic renal cell carcinoma

Sorafenib, an inhibitor of multiple tyrosine kinases including vascular endothelial growth factor receptor and Raf/mitogen-activated protein kinase, increases progression-free survival in metastatic renal cell carcinoma (RCC) compared with placebo. The efficacy and toxicity of combined sorafenib and radiation therapy (RT) in the treatment of RCC are unknown. This is a retrospective report of 3 consecutive patients with metastatic or locally recurrent RCC treated with palliative RT while undergoing sorafenib therapy. All 3 patients experienced disease progression on sorafenib and remained on the drug without dose reduction during the RT plus sorafenib regimen. They were followed for toxicity and response by clinical history, physical examination, and contrast-enhanced computed tomography scans. Soon after completion of palliative RT, all 3 patients experienced complete pain relief without the need for narcotic pain medication. Posttreatment imaging revealed partial response with > 50% regression of tumor in all patients. None reported significant acute or late side effects at follow-up of 3, 6, and 8 months after RT and sorafenib. In the 3 patients with recurrent or metastatic RCC in this report, the combination of RT and sorafenib was well tolerated and resulted in excellent clinical and radiologic responses. This combination is promising and requires further study.     

Taxanes and capecitabine in combination: rationale and clinical results

The clinical utility of capecitabine as a single agent in metastatic breast cancer has been demonstrated with significant responses seen in women already treated with anthracyclines and taxanes. A phase II study in older women with metastatic breast cancer demonstrated capecitabine to be an effective front-line therapeutic agent. Clinical trials of capecitabine in combination with the taxanes, paclitaxel and docetaxel, have been based on the observed upregulation of thymidine phosphorylase (TP) in preclinical studies. This taxane-mediated upregulation is synergistic, time dependent, and persists for up to 10 days. Studies of taxanes administered every 3 weeks with capecitabine have shown favorable antitumor responses and the combination of a taxane with capecitabine was favored over a taxane alone. The day-to-day administration of taxanes and capecitabine led to toxicity concerns, which have hindered their daily use. The administration of taxanes on a weekly schedule has demonstrated a more favorable toxicity profile (i.e., less myelosuppression), and initial studies in combination with capecitabine have demonstrated their utility in various solid tumors. Schedule optimization based on the upregulation of TP may result in a greater therapeutic index, thus allowing for the determination of the most advantageous way of combining these agents.     

Sentinel node biopsy in clinical stage 1 melanoma: rationale for restaging and follow-up

Lymph node involvement appears to be the most significant prognostic factor in patients affected by melanoma and has been shown to reduce the five-year survival by 40%. We studied 31 patients (15 M; 16 F; age range, 28-83 years) with clinical stage 1 (CS1) intermediate thickness (0.75-4 mm) melanoma. Scintigraphic examination of the nodes was performed in all patients, 29 of whom underwent surgical biopsy of the SN after 24 hours. Early images were acquired 5, 15 and 79 min and late images 60-180 min following perilesional injection of 2-4 microdoses of 99mTc-nanocolloid (15-20 MBq). A cobalt marker was used to project the SN on the skin surface which was later stained with indelible ink. For intraoperative localization we used a portable probe and perilesional injection of patent blue violet dye, which proved positive in 24/29 patients (83%). After surgery histological examination of the sentinel lymph nodes (SNs) (hematoxylin-eosin and immunohistochemistry) found positivity for metastatic cells in 6 patients. They all underwent elective lymph node dissection (ELND); five are N0+ and are currently undergoing supportive therapy with interferon alpha with an 8-24-month follow-up, while one N+ patient died 14 months after surgery. Follow-up (3-26 months) of N0- patients has not evidenced any locoregional recurrence so far. Only one case showed hematogenic metastases. This procedure might radically change the therapeutic approach to CS1 melanoma because it is simple, scarcely invasive, and shows a favorable cost-benefit ratio.     

Metastatic melanoma: chemotherapy

The incidence of cutaneous melanoma has been rapidly increasing, with an estimate of 47,700 new cases diagnosed in 2000 in the United States. In the early phase of its natural history, melanoma is cured in most cases by surgery, but once the metastatic phase develops, it is almost always fatal. The treatment of metastatic melanoma remains unsatisfactory. Systemic therapy has not been successful up to now, with very low response rates to single-agent chemotherapy. Polychemotherapy has increased the response rate (RR), without a significant improvement in overall survival. Immunotherapy alone is able to induce only a few durable complete responses (CRs). New chemotherapeutic and biologic agents are now available and promising combined approaches targeting the tumor by several different mechanisms are desirable and will probably represent the future modality of treatment.     

Radiotherapy for cutaneous malignant melanoma: rationale and indications

The use of radiation as adjuvant therapy for patients with cutaneous malignant melanoma has been hindered by the unsubstantiated belief that melanoma cells are radioresistant. An abundance of literature has now demonstrated that locoregional relapse of melanoma is common after surgery alone when certain clinicopathologic features are present. Features associated with a high risk of primary tumor recurrence include desmoplastic subtype, positive microscopic margins, recurrent disease, and thick primary lesions with ulceration or statellitosis. Features associated with a high risk of nodal relapse include extracapsular extension, involvement of four or more lymph nodes, lymph nodes measuring at least 3 cm, cervical lymph node location, and recurrent disease. Numerous studies support the efficacy of adjuvant irradiation in these clinical situations. Although data in the literature remain sparse, evidence also indicates that elective irradiation is effective in eradicating subclinical nodal metastases after removal of the primary melanoma. Consequently, there may be an opportunity to integrate radiotherapy into the multimodality treatment of patients at high risk of subclinical nodal disease, particularly those with an involved sentinel lymph node. Such patients are known to have a low rate of additional lymph node involvement, and thus in this group, a short course of radiotherapy may be an adequate substitute for regional lymph node dissection. This will be the topic of future research.     

Mohs surgery for melanoma: rationale, advances and possibilities

Mohs surgery (MS) is an effective technique for the removal of a variety of cutaneous neoplasms by virtue of its thorough assessment of margins. It has yet to become widely accepted for melanoma because recognizing melanocytes histologically in frozen section can be problematic. Recently, 'rapid' methods of immunohistochemistry have been developed that resolve this issue by staining the melanocytes in frozen section. In addition, some of the immunohistochemistry protocols that previously required up to 1 h now take 19 min or less. These technological enhancements for MS have removed some of the obstacles towards the acceptance of MS as a legitimate option for removal of melanomas, especially poorly demarcated lesions and lesions from the head and neck, the distal extremities and the genitalia. Experience thus far with MS for melanoma has shown lower recurrence rates and improved disease-specific survival compared with historical controls for standard excision, while at the same time minimizing the sacrifice of normal tissue.     

Cutaneous melanoma: prognosis and treatment results worldwide.

This first metanalysis of melanoma from treatment centers worldwide consisted of 15,798 patients with localized melanoma (stages I and II) and 2,116 stage II melanoma patients with nodal metastases. Comparisons of dominant prognostic variables showed consistent results from center to center, despite the heterogeneity of the patient population. Six of eight centers that performed a multivariate analysis ranked ulceration among the first three most dominant prognostic factors. Men had a higher proportion of ulcerated lesions than did women. There was a positive correlation between ulceration and thickness. Patients with melanoma of the scalp had a worse prognosis than did those with lesions of the face and neck; those with melanomas on the hands had a significantly worse prognosis than did those with lesions on the arms or legs. In this study, women had a statistically significant survival advantage over men. Their melanomas arose in more favorable sites, were thinner, and less ulcerative and had a lower stage of disease at presentation. Stage III melanomas were more common in males, thicker, and more ulcerated and had a nodular growth pattern. Patients with clinically occult nodal metastases detected by pathological examination and those with a single metastatic node fared the best. Five of six centers identified the number of metastatic nodes to be the most significant prognostic factor. Distant metastases (stage IV were analysed at only two centers, which found that the number and site of metastases appeared to be the dominant prognostic features of stage IV melanoma. When all factors were analyzed in a Cox regression analysis, the dominant factors for stage IV melanoma patients were (1) the number of metastatic sites, and (2) the remission duration. There were no histologic criteria of the primary melanomas that predicted the patient's clinical course once distant metastases had developed.     

The role of elective lymph node dissection in melanoma: rationale, results, and controversies

Elective lymph node dissection (ELND) for patients with clinically occult metastatic melanoma in regional lymph nodes has the goal of curing metastases with a surgical treatment. This is in contrast to the low probability for surgical cure in patients with clinically detectable lymph node metastases. The rationale for elective node dissection is based on a hypothesis that melanoma metastasizes sequentially via lymph nodes and then to distant sites. A subgroup of melanoma patients with high risk for regional node micrometastases but low risk for distant micrometastases has been identified from prognostic factors analysis of large patient series, as well as surgical results of nonrandomized clinical trials. However, two nonrandomized surgical trials have failed to show a survival benefit for ELND. These studies were largely performed in female patients with extremity melanomas and there were limitations that preclude a definitive conclusion. No randomized trials have been conducted involving melanomas of the trunk or head and neck. Two prospective randomized surgical trials are now being conducted in North America and in Europe. Until the results of these trials are available, physicians are encouraged to enter patients into these ongoing clinical trials or consider ELND in selected patients where the benefit-risk ratio justifies it. Factors to be considered in this decision include intermediate tumor thickness (ie, 1 to 4 mm thickness), anatomic site, histology (ulceration and growth pattern), and the risk of the operation in individual patient settings.     

Metastatic melanoma: an unusual presentation

In this report we describe a case of a malignant cutaneous melanoma metastasizing to the pleural surface and peritoneal cavity 5 years after surgical resection of the primary lesion. Malignant cutaneous melanoma is a very aggressive cancer able to metastasize anywhere in the body. Pleural secondary lesions represent a rare event described only in a small number of patients and the association with peritoneal localizations may suggest an uncommon pattern of spread that we discuss.     

Metastatic uveal melanoma: biology and emerging treatments

Uveal melanoma is the most common primary intraocular cancer in adults. Nearly half of primary uveal melanoma tumors metastasize, but there are currently no effective therapies for metastatic uveal melanoma. The recent discovery of mutations that underlie uveal melanoma metastasis, growth, and survival provide a key to the molecular understanding of this disease. Much work is now underway to leverage this knowledge to develop effective therapies. This review summarizes recently discovered molecular features of uveal melanoma and therapies being explored to capitalize on this knowledge.     

Preoperative chemoradiation for locally advanced rectal cancer: rationale, technique, and results of treatment

Over the past decade, 392 patients with stage II and III rectal cancer have been managed with preoperative chemoradiation and surgery at the M. D. Anderson Cancer Center (MDACC). Aggressive surgical techniques such as total mesorectal excision, proctectomy with coloanal anastamosis, and multivisceral excisions have been used. Initial pelvic chemoradiation is also used in patients who present with metastases. Preoperative chemoradiation followed by surgery has resulted in excellent sphincter preservation (SP) and pelvic control with minimal acute, perioperative, and late morbidity. SP has been achieved in greater numbers of patients over the past 3 years due to the increased use of coloanal anastamosis in very low tumors. There has been no increase in pelvic failure or perioperative morbidity with this practice. Patients with clinical T4 disease have significantly worse pelvic control. An assessment of the impact of CB on pelvic control and survival requires further follow-up. Poor differentiation and poor response to preoperative therapy predict a worse overall survival. Durable symptom control without colostomy has been achieved using initial chemoradiation in patients who present with metastases. Aggressive bowel management and skin care can minimize hospitalization and treatment interruption due to acute toxicity. Multidisciplinary therapy using preoperative chemoradiation and aggressive surgery has resulted in excellent SP and pelvic control. However, more effective systemic therapies are needed, especially for patients who do not respond well to preoperative chemoradiation.     

Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale

PurposeIn 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance.Patients and methodsWe analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples.ResultsIn HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013).ConclusionsOur findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.     

Metastatic nasopharyngeal carcinoma: clinical study and therapeutic results of 95 cases]

PURPOSE: The objective of this retrospective study was to discuss the epidemioclinical criteria and the therapeutic results of metastatic nasopharyngeal carcinoma. PATIENTS AND METHODS: The current study concerned 95 patients with histologically proven nasopharyngeal carcinoma who were metastatic at diagnosis or who had developed late metastasis. We reviewed the epidemioclinical records of all the patients. Patients were treated with chemotherapy (BEC regimen: bleomycin, epirubicin and cisplatin or PBF regimen: bleomycin, 5-fluorouacil and cisplatin) and radiotherapy of pauci metastatic localizations (single or double) or bone metastasis with high risk of compression or fracture+/-associated with locoregional radiotherapy for patients who were metastatic at diagnosis. Response was assessed according to the WHO criteria. Overall survival was calculated according to the Kaplan-Meier method. A long-term disease-free survival was defined from 36 months. RESULTS: There were 34 patients who were metastatic at diagnosis and 61 patients who had developed late metastasis. The mean age was 41.5 years (sex-ratio: 3.1). Bone metastases were the most frequent (83%). Objective and complete response rates were respectively 75% and 70%, and 32% and 16% for BEC and PBF regimens. Twenty-five patients received radiotherapy for pauci metastatic localizations, among whom 19 patients who were metastatic at diagnosis received locoregional irradiation. The overall survival probability was of 15% for three years. Eleven patients were long survivors (extremes: 36 and 134 months). CONCLUSION: Therapeutic results were comparable to those reported in other series using platin combination chemotherapy. Radiotherapy of metastasis yielded to long-term survival.     

Commentary: publishing cancer clinical trial results: a scientific and ethical imperative

This editorial further discusses the low number of oncologic clinical trials published in the peer‐reviewed literature and reports on the development by the National Cancer Institute of its own clinical trials database to capture all administrative and outcomes data for all clinical studies performed at National Cancer Institute–supported institutions.