ONCOLOGY Vol 24 No 11

Noni is an evergreen plant prevalent in Southeast Asia, Australia, and the Polynesian islands. It is used in traditional medicine for wound healing, infections, skin conditions, diarrhea, and as a tonic. Noni products have gained worldwide popularity over the past 2 decades and are aggressively marketed for immunostimulation and for treatment of chronic fatigue syndrome and cancer.Preliminary data from in vitro and animal studies suggest immunomodulatory, antioxidant, and antitumor properties. However, hepatotoxicity and hyperkalemia have also been reported with noni use.

In early 2008, based on the results of its E2100 trial, which showed significant improvements in progression-free survival when combined with paclitaxel, Avastin (bevacizumab) gained an FDA accelerated approval. Median progression-free survival in the Avastin arm was 11.3 months compared with 5.8 months for paclitaxel alone (although overall survival in the two arms was similar). However, final approval would be dependent on subsequent trials showing similar degrees of benefit. When two additional trials were submitted for review, both showed significant improvements in progression-free survival, but again with no difference in overall survival. Subsequently, on July 20th of this year, the Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 not to recommend permanent approval of Avastin as first-line therapy in advanced breast cancer.

Clinical outcomes data for all of oncology include those from trial after trial demonstrating poor outcomes in older patients with cancer. Whether these are the result of limited biologic reserve, poor performance status, or inherently worse biological disease at the time of diagnosis, such age-based disparities have continued unabated for decades. However, for the first time, older patients with multiple myeloma (MM) are starting to enjoy the kinds of remission durations and overall survival (OS) seen in younger patients. In this review by Dr. Harousseau, we see that through the use of regimens such as MPV (melphalan and prednisone plus bortezomib), MPT (melphalan and prednisone plus thalidomide), MPR (melphalan and prednisone plus lenalidomide), VMPT (bortezomib, melphalan, prednisone, and thalidomide), and Rd (lenalidomide and low-dose dexamethasone), we can begin to provide older patients with MM with a median OS approaching the 4- to 5-year mark-a far cry from the median OS of 2.5 to 3 years seen with MP just 15 years ago. So what are the remaining hurdles and challenges to be addressed in the upcoming 10 years?

Ganti and colleagues have provided a brief review on the diagnosis of small-cell lung cancer (SCLC) and the roles of chemotherapy and surgery in its management. Notably, in the past three decades, the most significant progress in the treatment of SCLC has mainly involved the use of radiotherapy. Thus, to complement their assessment, we will provide an overview of the role of radiation in the management of limited-stage and extensive-stage SCLC.

Small-cell lung cancer (SCLC) is a pathologically distinct malignancy of the lung, characterized by rapid growth, propensity for early metastatic spread, and responsiveness to chemotherapy and radiation. Despite its generally good initial response, the relapse and subsequent mortality rate remain very high. Only 3% to 8% of all patients survive 5 years, and median survival for extensive stage disease is 8 to 13 months.[1,2]

This paper by Drs. Bhayani, Holsinger, and Lai describes a new approach to an old problem. Advances in the management of head and neck cancer over the past few decades have been made predominantly in the area of non-surgical therapy. Starting with the Veterans Affairs Cooperative Trial for laryngeal cancer in the early 1990’s,[1] advances in the administration of chemotherapy and radiation therapy have enabled patients to forego traditional extensive resections that compromised speech and swallowing function.[2] The advances in combined chemoradiation for advanced head and neck cancer have come with a detriment to some patients in survival and quality of life.[3] Effective treatment, but with decreased morbidity was needed.

The role of radiation therapy (RT) in lung cancer is long established; some of the earliest Radiation Therapy Oncology Group reports dealt with non-small cell lung cancer (NSCLC).[1,2] More recently, the advent of stereotactic body RT (SBRT) techniques has provided significant local control rates after focused treatment of selected small metastases and inoperable early stage lesions.[3,4] Our center has been in the forefront of examining SBRT and its role in central [5] or bilateral [6] lesions, its effect on PET imaging [7] and pulmonary function testing,[8] and subsequent frequency of brachial plexopathy,[9] chest wall toxicity,[10] or pneumonitis.[11] Still, even this highly conformal technique comes with potentially significant dose to adjacent normal tissue. This is in the context of an emerging appreciation for the pulmonary consequences of elevated mean lung dose,[12] or V5 after pneumonectomy.[13] For each lung cancer patient requiring RT, an effective mechanism to deliver dose to the tumor while minimizing dose to uninvolved lung is called for. Enter protons.

In the conclusion to the article “Proton Radiation Therapy for Lung Cancer: Is There Enough Evidence?” Dr. David Bush puts his finger on the critical issue underlying most debates about the value of new medical technologies. He notes that “The evidence required to bring new technology into clinical practice is poorly defined.”[1] In the specific context of this article, the answer to the question of whether or not there is enough evidence depends entirely on how one chooses to define “enough.” Some experts believe that biological modeling based on dose distributions is sufficient to conclude that proton therapy improves health outcomes. Others have argued that the evidence is only adequate once randomized clinical trials have been completed to directly compare alternative interventions. Whatever one’s position on this issue, the lack of clarity on the question of adequacy of evidence is a major contributor to the gaps in knowledge about the comparative effectiveness of many widely used clinical interventions. Accelerating the rate at which this knowledge is generated will require a serious and sustained effort to define these evidence thresholds. This would allow more energy to be channeled into generating the needed evidence and less energy to be devoted to debating whether or not the evidence we have today is good enough.

Just as in recent years attitudes and treatment therapies have changed regarding non–small-cell lung cancer (NSCLC), it is time that the same occur for its small-cell counterpart. Although treatment for advanced-stage small-cell lung cancer (SCLC) is fairly standardized, there remain a number of controversies that have yet to be clarified by evidence-based data.

A series of promising new advances have emerged in H&N oncology in recent years. Among these are the advancement of highly conformal radiation delivery techniques (e.g. IMRT, protons); the successful introduction of molecular targeted therapies (e.g. cetuximab); the recognition of HPV as a powerful prognostic biomarker; and the development of minimally invasive surgical techniques. The application of transoral robotic surgery (TORS) in H&N cancer is reviewed by Bhayani et al in this issue of ONCOLOGY[1].

Proton radiation for cancer offers the ability to conform the high-dose region of radiation therapy to the tumor while reducing the dose of radiation to adjacent normal tissues. In lung cancer, this equates to greater sparing of uninvolved lung, heart, esophagus, and spinal cord. Sparing these normal tissues permits the delivery of higher-radiation doses to the tumor. Studies that compare the distribution of radiation doses for lung cancer show that proton radiation is superior, even when factors such as respiratory motion are considered. Clinical experience confirms the feasibility of proton radiation for early-stage non-small-cell lung cancers, and clinical trials are being conducted in locally advanced tumors: To date, evidence indicates that proton radiation should be further explored.

The article presented by Bhayani, Holsinger, and Lai thoroughly evaluates the emergence of transoral robotic surgery (TORS) as a technique in the field of otolaryngology. Transoral approaches to the upper aerodigestive tract, whether for diagnostic or therapeutic purposes, represent core tenets of the discipline and formed one of the bases for the inception of the specialty. Innovations and refinements in optics and materials have steadily increased the view, reach, and, consequently the effectiveness of the endoscopic surgeon with each passing decade. In the past thirty years, the introduction of the laser has further enhanced the capabilities of the surgeon, augmenting treatment options beyond open tumor resection and chemoradiation. The introduction of the daVinci robot is an incremental step in the development of techniques that have been evolving over the past one hundred and twenty years.

Despite a decreasing incidence in the United States, small-cell lung cancer (SCLC) remains a major clinical problem, with approximately 30,000 new cases each year. The diagnosis of SCLC is usually not difficult. The Veterans Administration Lung Study Group (VALSG) staging system is less accurate than the American Joint Committee of Cancer tumor-node-metastasis (TNM) system (7th edition) at predicting survival in SCLC, especially in lower stage disease. Surgery has not played a major part in the management of SCLC, but emerging data suggest that resection may have a role in earlier stage disease. While the frontline treatment of SCLC has not changed significantly in the past decade, newer agents that are currently being investigated provide hope for better treatment of relapsed/refractory disease for the future.

The evolution of surgical oncologic technology has moved toward reducing patient morbidity without compromising oncologic resection. In head and neck surgery, organ-preserving techniques have paved the way for the development of transoral techniques that remove tumors of the upper aerodigestive tract without external incisions and potentially spare the patient adjuvant treatment. The introduction of transoral robotic surgery (TORS) improves upon current transoral techniques to the oropharynx and supraglottis. This review will report on the evolution of robotic-assisted surgery: We will cover its applications in head and neck surgery by examining early oncologic and functional outcomes, training of surgeons, costs, and future directions.

Until recently, standard treatment of multiple myeloma (MM) in elderly patients who were not candidates for autologous stem cell transplantation was with the combination of melphalan plus prednisone (MP). Novel agents (thalidomide, lenalidomide, bortezomib) are dramatically changing frontline therapy of MM. Randomized studies have shown the superiority of adding one novel agent to MP, either thalidomide (MPT) or bortezomib (MPV). The combination of lenalidomide with low doses of dexamethasone is another attractive alternative. Recent results show that maintenance therapy with low-dose lenalidomide may prolong progression-free survival. The objective of these improved treatment regimens should be to achieve complete response, as in younger patients. However, toxicity is a significant concern, and doses of thalidomide and of myelotoxic agents should be reduced in patients who are older than 75 years or who have poor performance status. Weekly bortezomib appears to induce severe peripheral neuropathy less frequently than the same agent administered twice weekly. Autologous stem cell transplantation is feasible in selected fit patients over 65 years of age, and its results are improved by the addition of novel agents before and after high-dose therapy. However, considering the progress in non-intensive therapy, autologous transplantation should not currently be offered to elderly patients outside of a clinical trial.

The variety of treatment options available to patients of all ages who have multiple myeloma has improved considerably in the past decade. However, elderly patients have benefited more than patients of other ages. Because elderly patients, as a group, are usually not offered autologous stem cell transplant (ASCT) as a treatment option, they have been unable to benefit from the wide application of this technique, first introduced in the late 1980s. In the past 8 years, however, thalidomide, bortezomib, and very recently lenalidomide, when combined with conventional doses of alkylators and corticosteroids, have produced marked improvements in progression-free survival (PFS) and overall survival (OS) in elderly patients. Harousseau has thoroughly reviewed the important studies documenting these benefits for this population.