The past year has seen an explosion in the development of immune-oncology (IO) treatments for cancer. In solid tumors, immune-checkpoint blocking antibodies are being explored in many tumors while recent reports from the American Society of Hematology meeting suggest that immune-checkpoint blockade and adoptive cellular transfer will also have an important role in hematologic malignancies. These treatments are for the most part much less toxic than historical combination chemotherapy regimens and ad- ditionally appear to have the potential for long-term durable response. Clearly, IO has a significant and expanding role in cancer treatment.

Despite the recent amazing success and hype surrounding IO, immunotherapy for cancer is not at all a new concept. Cancer vaccines and cytokines have been of interest for decades. Unfortunately, the limited success observed with these approaches made them relevant only to a small group of patients—predominantly melanoma, renal cell carcinoma, and patients who had progressed through standard chemotherapies. The one significant exception to this is the field of hematologic bone marrow transplantation where the utility of the approach has been predicated on inducing an anti-tumor effect by the transplanted immune system.

Moving beyond transplant however, it appears that we are on the cusp of an age of IO therapy drug development in all cancers. In solid tumors, immune-checkpoint blocking antibodies, such as anti-CTLA4 (ipilimumab), anti-PD1 (nivolumab, pembrolizumab) and anti-PD-L1 (MPDL3280a) have or are close to becoming the standard of care for melanoma, bladder, and lung cancers and promising results have been observed in several other tumors types. In fact, multiple anti-PD1 or anti-PD-L1 agents have been granted breakthrough status and are likely to come into clinical practice within the next few months.

Similarly in hematologic malignancies, especially Hodgkin’s lymphoma, previously unknown clinical activity has been observed in refractory patient populations.

 Immune-checkpoint blocking antibodies are only part of the story, however, as other immunotherapies have also shown impressive results. Examples include bispecific antibodies, such as blinatumomab, and antibody drug conjugates (ADCs), such as brentuximab vedotin, demonstrating marked activity in chemotherapy and stem cell transplant refractory patient populations. In solid tumors, antibody drug conjugates are also changing the standard of care with T-DM1 becoming an important therapy in breast cancer, and other molecules such as glenbatumumab in melanoma, suggesting a potentially important role in the future. Finally, adoptive cellular therapy with chimeric antigen receptor (CAR) T-cells has received breakthrough status for acute lymphocytic leukemia and CARs for other hematologic malignancies as well as some solid tumors are rapidly being developed.

Clearly then, IO therapy is revolutionizing cancer therapeutics and may be positioned to become the underlying backbone of therapy in all cancers. A limitation of further development, however, is that a substantial proportion of cancer patients still do not respond to these agents and much work remains to determine both why this is the case and what measures may be taken to facilitate a more robust immune response in these patients.

Integral to understanding both of these issues will be the development of reliable biomarkers of anti-tumor immune activation and treatment response. With immunotherapies such as ADCs and CAR T-cells, this is less of an issue as the biomarker target is an essential element to the drug design. That being said, the number of common, tumor specific (or significantly overexpressed) antigens that can facilitate the development of these treatments is likely limited. In contrast, biomarkers of effect for immune-checkpoint blocking antibodies have been difficult to develop to date. There was initial optimism that expression of PD-L1 in the tumor microenvironment may be a useful biomarker. Unfortunately, the current generation of assay technology certainly does not support this, however, given that approximately 10% to 20% of patients whose tumors test “PD-L1 negative” have been shown to experience Response Evaluation Criteria In Solid Tumors (RECIST) responses.

Given this, better predictive and prognostic biomarkers are needed. Recent studies have suggested that perhaps a more individual tumor specific biomarker development strategy may be useful. A recent elegant report detailed that nearly all patients responding to the anti-PD1 antibody pembrolizumab had expression of PD-1/PD-L1 in a population of T cells existing specifically at the tumor margin.

 Therefore, PD-L1 testing would need to take into account the anatomy of the tumor and biopsy techniques would need to be adapted as such. Alternatively, a model of understanding the immune response in the context of the tumor microenvironment has been proposed in which tumors can be determined as having an “inflamed” or “noninflamed tumor phenotype.” This phenotype can be predicted by gene expression profiling of a 13-gene signature from a tumor biopsy and has been very highly correlated with response to various immunotherapies from vaccines, cytokines, and immune-checkpoint blocking antibodies.

Returning to the role of IO in cancer therapy—perhaps it’s time to consider flipping our standard paradigm of adding new drugs, such as IO agents, to existing treatments and instead consider whether the existing treatments can augment the immune response. An emerging field of preclinical research suggests that in fact this may be the best way to use the drugs we have already. Studies detailing the utility of radiation in augmenting immunotherapy

 or BRAF inhibitor driving a T cell infiltrate into the tumor

suggest that there is an intersection between our existing treatments and the immune response. Other examples including VEGF-directed agents modifying immunosuppressive cell populations

 and “immunogenic” chemotherapies priming an immune response.

With the development of these exciting new categories of IO therapies, the future seems bright for the development of vastly more efficacious treatment strategies that are much less toxic. Those treatment regimens will likely include a little of the old (chemotherapy, radiation, etc) and a little of the new (immune-checkpoint blockade, CAR T-cells, etc). To reach this future, however, the oncology community will have to consider new models for drug development. The days of conducting clinical trials by adding new drug X to old drug Y just because we have them should be abandoned. Instead, we need scientifically justified and rationale clinical trials. An example of such a trial might be 1 week versus 1 month of drug X, in combination with immunotherapy drug Y, to determine the maximal immune effect achieved. With the proliferation of agents for cancer over the past few years, including both targeted and immunotherapies, the number of clinical questions surrounding optimal sequencing and combinations approaches infinity. Therefore, we need a future of smart, biomarker driven trials to guide the optimal treatment of our patients.

		Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. 

		Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. 

		Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. 

		Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. 

		Falchook GS, Long GV, Kurzrock R, et al. Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). 

		Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. 

		Hato SV, Khong A, de Vries IJ, et al. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. 

Articles

With the proliferation of agents for cancer over the past few years, including both targeted and immunotherapies, the number of clinical questions surround- ing optimal sequencing and combinations approaches infinity.

Will Immuno-oncology Become the Backbone of Treatment for all Cancers?

In the United States in 2010, it was estimated that there were more than 1.5 million new cancer cases and 569,490 deaths from cancer.

 In patients with advanced cancer, pain is the most commonly reported symptom with a prevalence of 60% to 70%, and unrelieved pain is the most feared symptom in 70% to 80% of these patients.

 Despite advances in pain management and palliative care, intractable cancer pain remains a significant clinical, social, and financial burden in treating the oncologic population.

In advanced stages of cancer, tumors are often incurable and treatment is targeted to controlling pain symptoms and improving a patient’s quality of life.

 Often radiotherapy, chemotherapy, targeted therapy, and surgery are all used to treat and palliate cancers.

 According to the World Health Organization (WHO) analgesic ladder, pharmacologic management is the mainstay for malignancy-related pain.

 However, when patients develop tolerance or side effects to analgesics, interventional pain techniques can better manage a patient’s pain and improve the patient’s quality of life.

In this article, we introduce the reader to various causes of cancer pain, discuss pharmacologic management, and focus on interventional techniques for patients suffering from intractable pain secondary to cancer.

The presence of the tumor itself can cause pain in 4 different ways: (1) nociceptive pain, caused by direct activation of nociceptors (eg, stretched skin or bone), (2) inflammatory pain, caused by release of chemical modulators (ie, growth factor, bradykinin-1, substance P) in response to tissue damage and inflammation resulting in increased nociceptor sensitivity, (3) neuropathic pain, caused by injury of peripheral or central nerves by direct tumor infiltrative etiology or damage by chemotherapy, and (4) functional pain, caused by a derangement in central processing of pain (Table).

 Although most patients with cancer receive multimodal treatment, understanding the different causes of malignancy-related pain can guide targeted pharmacologic and interventional treatments.7

In 1986, the WHO first introduced an analgesic ladder as a pharmacologic algorithm for addressing the management of malignancy-related pain.

 Studies have shown that application of the 3-step approach to administering an appropriate drug at the right dose at the right time is inexpensive and 80% to 90% effective

 The first step of the WHO ladder includes non-opioid analgesics and adjuvant medications, which are often used in combination.

 Commonly used medications to treat nociceptive and inflammatory causes of cancer pain include nonsteroidal anti-inï¬‚ammatory drugs, acetaminophen, and corticosteroids. Adjuvant medications, such as antidepressants (eg, nortriptyline and duloxetine) and anticonvulsants (eg, gabapentin and pregabalin) are also used to treat neuropathic cancer pain.

 Bisphosphonates and monoclonal antibodies (ie, denosumab), may improve pain in patients with bony metastases or may delay worsening of pain control.

 Baclofen and benzodiazepines can help treat pain associated with spasticity.

The second step of the analgesic ladder includes using weaker opioids, such as codeine, tramadol, hydrocodone, and oxycodone for mild to moderate pain

 The third step includes stronger opioids, such as morphine, hydromorphone, oxymorphone, fentanyl, and methadone for severe pain.

 Transdermal opioids are safe, effective, and produce significantly fewer side effects than oral medications when used for moderate-to-severe cancer pain. However, transdermal opioids require a long lag period for dose stabilization and elimination.

Patient Selection for Interventional Techniques Patient selection is important in determining who should pursue interventional techniques for pain management. Patients with pain refractory to medical management or with intolerable side effects to systemic pain medications should be considered for interventional procedures. Accounting for disease-related survival is crucial in deciding if a patient is a suitable candidate for a particular procedure. Patients with shorter life expectancy may be more appropriate for less expensive procedures (eg, intercostal nerve block). However, other procedures (eg, intrathecal pump placement) are generally reserved for patients with longer life expectancy. In performing certain procedures, the cost and benefits of the interventional techniques should be weighed against risks of the procedures, especially for patients with active infections or bleeding diathesis.

During the past decade, advances in chemotherapy, radiotherapy, and other cancer treatments have improved survival but have also resulted in more complex syndromes of cancer pain.

 Recent studies indicate that 20% to 40% of cancer pain is not adequately relieved by solely applying the analgesic ladder.

 In addition, the role of high-dose opioids in pain management is under scrutiny. Thus, new interventional approaches are necessary to help control a patient’s pain when the 3-step WHO analgesic ladder proves limited. These new approaches may allow for better control of a patient’s pain symptoms.

Interventional techniques target many different neural mechanisms involved in cancer pain.

 Since patients can undergo various treatment options to block pain transmission anywhere from peripheral nerves to the spinal cord, interventional pain strategies are divided between peripheral and neuraxial interventions.

Although early application of interventional techniques is encouraged, a combination of both pharmacologic and interventional therapy may provide patients with superior quality of analgesia over either strategy alone.

Peripheral therapies block pain transmission from peripheral and sympathetic nerves involved in afferent somatic pain signals or sympathetic and visceral afferent pathways. These nerves can be blocked using local anesthetics that provide temporary diagnostic relief. Once a diagnostic block has been shown to be effective, prolonged pain relief can be achieved by performing blocks using steroids in combination with local anesthetics and/or neurolytic techniques (ie, cryoablation,

Peripheral Nerves: Targeted nerve blocks are used when pain is limited to the distribution of specific nerves. The targets for these blocks include: trigeminal nerve branches, sphenopalatine ganglion, brachial plexus, lumbar plexus, sacral plexus, intercostal nerves, ilioinguinal and iliohypogastric nerves, and saphenous and pudendal nerves. By using image guidance (eg, ultrasound, fluoroscopy, and computed tomography), the accuracy of the procedure can be improved and the rate of complications can be limited.

However, patients are still at risk for sensory-motor deficits and deafferentation pain after neurolysis.

 Because of the risk of motor deficits causing loss of functionality, it is recommended to perform peripheral neurolytic blocks on primarily sensory nerves (eg, ilioinguinal nerve) compared with mixed motor-sensory nerves (eg, brachial plexus).24 Another complication of neurolysis is deafferentation pain, which appears to result from aberrant nerve fiber regeneration and neuroma formation. Deafferentation pain can occur from any procedure resulting in neurolysis.

 Local and regional sympathetic blocks are used to block sympathetically mediated pain signals involving the viscera. These blocks include: stellate ganglion block, celiac plexus block, lumbar sympathetic and splanchnic nerve block, superior hypogastric plexus block, and ganglion of Impar block. Neurolysis can interrupt efferent sympathetic fibers, afferent pain fibers traveling in the sympathetic chain, and somatic or visceral pain fibers.

 The stellate ganglion block is used to treat neuropathic pain of the upper extremities and chest (ie, cancers of the breast, thorax, head/neck), postradiation pain, postoperative neuropathy, atypical neuropathic facial pain, and phantom limb pain. The ganglion is formed by fusion of the inferior cervical sympathetic ganglion and the first thoracic sympathetic ganglion and is located anterior to the transverse process of C6 to C7, superior to the neck of the first rib, and below the subclavian artery. Complications of the block include Horner’s syndrome (eg, ptosis, miosis, conjunctival injection, ipsilateral facial warmth, anhidrosis, and ipsilateral vasodilation).

The celiac plexus block (Figure 1) is used to treat pain related to pancreatic cancer, bile duct cancer, gastric cancer, and primary liver neoplasm, and for visceral pain originating from all upper abdominal structures. The plexus is located at the level of the upper part of the first lumbar vertebra and surrounds the celiac artery. It lies between the suprarenal glands, in front of the crura of the diaphragm and abdominal aorta, and behind the stomach and omental bursa. Complications of this block include hypotension, diarrhea, the need for intravascular injection, spinal/epidural injections, back/shoulder pain, leg weakness, sensory deficits, paresthesias, and paraplegia.

Lumbar Sympathetic and Splanchnic Nerve Block:

 The lumbar sympathetic and splanchnic nerves can be targeted for pain from the lower abdominal structures, lower extremities, and for ipsilateral pelvic visceral pain. The lumbar sympathetic ganglion is located along the anterolateral surface of the lumbar vertebral bodies and anteromedial to the psoas muscle. The vena cava lies just anterior to the right sympathetic chain and the aorta lies anterior to the left sympathetic chain. The splanchnic nerves and lumbar splanchnic chain are usually medial to the lumbar sympathetic chain and may travel around the large blood vessels of the abdomen. Complications from this block include hypotension, back/shoulder pain, intravascular injections, spinal/epidural injections, genitofemoral neuralgia, psoas, and lumbar plexus damage.

The superior hypogastric plexus block is used to treat pain from the entire pelvis with the exception of the Fallopian tubes and ovaries. It is useful in treating pain from cervical cancer or any type of pelvic pain (eg, bladder spasm/pain, testicular pain), except for ovarian pain. The plexus is located in the retroperitoneal space, starts at the lower part of the fifth lumbar vertebral body and reaches the upper part of the first sacral vertebral body, close to the aortic bifurcation. It transfers visceral impulses from the upper vagina, cervix, uterus, bladder, and right colon to the dorsal horns of the spinal cord through sympathetic thoracic lumbar fibers. Complications from this block include infection, damage to the aorta/iliac vein/lumbar nerves, and retroperitoneal bleeding.

 The ganglion of Impar block is used to treat rectal pain, perineal pain, rectal spasm, or coccydynia. The ganglion is located anterior to the sacrococcygeal junction where the 2 pelvic sympathetic trunks converge at the cranial base and travel retroperitoneal to form the solitary median ganglion. It is usually targeted anterior to the sacrococcygeal or coccygeal ligament. Complications from this block include infection, accidental perforation of the rectum, impaired bladder or bowel function, impaired sexual function, impaired motor or sensory function, and postinterventional neuralgia.

Neuraxial techniques focus on directly blocking modulation of afferent, nociceptive fibers, interneurons, and ascending fibers of the spinal cord in the epidural or intrathecal space. Epidural and intrathecal opioids, steroids, and local anesthetics are used to provide pain relief with fewer side effects than oral or parenteral medications.

 These agents can also be used in tunneled epidural catheters and intrathecal pumps.

 Neuromodulation (ie, transcutaneous electric nerve stimulation and spinal cord stimulation) is another technique that can provide pain relief to patients with cancer.

: Intrathecal neurolysis is used to treat intractable cancer pain in a localized area and is thought to be more effective in treating visceral and somatic pain, and less effective in treating neuropathic pain.45 Alcohol and phenol are injected into the intrathecal space with the goal of producing disruption in sensory transmission while preserving motor function, targeting the dorsal rootlets.45 These neurolytic blocks produce an opioids-sparing analgesic effect and decrease the dose of opioid medications used. Side effects from these techniques can include bladder and rectal sphincter dysfunction, but side effects depend on the area of injection.

 For patients with pain that becomes increasingly difficult to manage, intrathecal drug delivery systems are an effective option for pain relief.

 Compared with conventional pharmacologic management, prospective randomized studies have shown improved pain relief and decreased adverse effects in chronic pain patients using intrathecal drug delivery. The placement of opioids delivered by pump to the intrathecal space provides pain relief and improves quality of life for patients with cancer.

Intrathecal drug delivery is used to treat visceral pain from pancreatic, liver, and stomach cancer, and somatic pain from bone metastases.

 Intrathecal medications have been shown to be effective in treating neuropathic pain (ie, postherpetic neuralgia or cancer-related plexopathies), and in some cases, improved survival when compared with conventional medical management.

Intrathecal opioids are about 100 times more potent than intravenous opioids.

 Because of the long duration of action, effectiveness, and ease of use, morphine is the most commonly used medication for intrathecal analgesia. Other medications used intrathecally include hydromorphone, fentanyl, bupivacaine, ziconotide, clonidine, sufentanil, ropivacaine, buprenorphine, midazolam, meperidine, and ketorolac. Experimental agents, such as gabapentin, octreotide, neostigmine, and adenosine, have all been used, though not necessarily shown to be effective.

Before placing an intrathecal pump, the patient undergoes a trial to establish pain relief and to select the most appropriate medications and dosages to be used with the pump. Normally, the trial consists of a single injection or continuous infusions into the epidural or intrathecal space. If the patient has a positive trial, intrathecal drug delivery systems are placed either as a percutaneous short-term intrathecal catheter, a long-term tunneled intrathecal catheter, or an implantable infusion pump and catheter.

 An implantable infusion pump and catheter requires periodic refilling of the pump and assessment of the patient for adequate pain relief and possible complications after implantation of the pump, such as granuloma formation or infections. These patients also have a patient-controlled device providing additional boluses to provide pain relief and improve quality of life.

: Since placement of intrathecal drug delivery systems is expensive and there is a risk for serious complications, including granuloma formation and post- dural puncture headaches, tunneled epidural catheters may be theoretically more beneficial for patients with a limited life expectancy. Unfortunately, the disadvantage of epidural port systems is that they become more expensive when survival is prolonged (>3 months). There is limited data for the use of tunneled epidural catheters via a percutaneous port in treating malignancy-related pain.

Transcutaneous Electrical Nerve Stimulation:

 Transcutaneous electrical nerve stimulation (TENS) is a noninvasive intervention used to treat a variety of acute and chronic pain disorders. The mechanism of action of TENS therapy is thought to be related to the gate theory of pain. In this theory, there is a ‘gating mechanism’ in the dorsal horn of the spinal cord that controls the transmission of pain signals. By stimulating large-diameter afferent fibers, the ‘gate’ becomes ‘closed’ and the perception of pain is reduced. The advantages of TENS devices are that they are portable, easy to use, and have few adverse effects. Unfortunately, the use and clinical benefit of TENS devices for oncology and palliative care patients with severe cancer pain remains controversial, and it is unclear which patients benefit from this technique.

 Spinal cord stimulation (SCS) (Figure 2) is a minimally invasive approach to treat neuropathic and nociceptive pain. It is mostly used in patients suffering from chronic pain states, such as post-laminectomy syndrome or complex regional pain syndrome. However, since neuropathic pain is a common component of malignancy-related pain, some researchers suggest that SCS may be a valuable technique in patients suffering from intractable cancer pain.

The use of SCS for the treatment of intractable cancer pain has many advantages. Patients can have a trial of the SCS prior to permanent implantation. Implanting the SCS system is a minimally invasive procedure that can be performed in an outpatient setting. There are few side effects to placement and the spinal cord stimulator can be removed if the SCS is no longer effective or fails to provide the anticipated level of pain relief. The main limitation of SCS is that it is not effective in all patients. Most studies demonstrate only 50% to 60% of patients achieve at least a 50% reduction in pain, and there are no randomized controlled trials addressing the efficacy and safety of SCS in patients with cancer. Another serious limitation with placement of spinal cord stimulators in patients with cancer is that most current devices are not compatible with magnetic resonance imaging (MRI) (although newer devices have some FDA-approved MRI compatibility). Because many patients with cancer need continuous surveillance as part of their treatment, SCS may interfere with a patient’s therapeutic course. Complications of placement in SCS include lead migration, lead connection failure, lead breakage, pain at the generator site, dural puncture, bleeding, and infection.

 Vertebral collapse caused by metastatic disease is a frequent source of pain in cancer patients.3 Vertebroplasty and kyphoplasty are interventional pain procedures of the spine, in which polymethylmethacrylate is injected through a needle into a weakened vertebra with the goal of relieving back pain and symptoms of cord compression.

 Besides pain relief, these procedures provide vertebral stability and prevent progression of the fracture or further vertebral body collapse.54 The risks of these procedures are related to cement extravasations, which can lead to radiculopathy by causing pressure on the spinal cord or nerve roots, cement embolism, infection, and death.3 Unfortunately, studies of these procedures have failed to show significant reduction in pain over control.

 One randomized controlled trial demonstrated balloon kyphoplasty to be superior to nonsurgical management for cancer-related vertebral compression fractures.

Patients with advanced cancer can present with severe intractable pain. Although following the WHO analgesic ladder can help treat most patients, some individuals may need additional interventional pain therapies for pain relief and improvement in their quality of life. Interventional techniques should be used in conjunction with pharmacologic management for treatment of cancer pain symptoms. As patient survival with cancer improves, treating patients with cancer pain syndromes becomes more complex and difficult. Determining which interventional technique to try involves careful understanding of the risks and benefits of each procedure. Although more evidence is needed to determine when and how to apply these interventional pain therapies, utilizing interventional techniques and targets will allow for better pain control in our oncologic patients, often with fewer systemic side effects.

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			Heo BH, Pyeon TH, Lee HG, et al. Epidural infusion of morphine and levobupivacaine through a subcutaneous port for cancer pain management. Korean J Pain. 2014;27(2):139-144.

			Miller D, Fenton D, Dion J. Vertebroplasty. In: Image-Guided Spine Intervention . Fenton D (Ed.). Saunders, Philadelphia, PA, USA, 189-223 (2003).

			Buchbinder R, Osborne RH, Ebeling PR et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N. Engl. J. Med. 2009;361(6):557-568.

			Kallmes DF, Comstock BA, Heagerty PJ et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361: 569-579.

			Berenson J, Pflugmacher R, Jarzem P et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12:225-235.

Update on the Management of Pain in Patients With Advanced Cancer

With 8 therapies approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma (RCC), practitioners are faced with the challenge of selecting the most appropriate therapies for their patients within this crowded therapeutic landscape.

When selecting a treatment plan for a previously untreated patient with advanced RCC, practitioners must frequently think beyond the first line of therapy and approach the patient with a possible sequence of therapies already in mind. Sequential therapy with various single agents is a practical reality for most patients with advanced RCC for numerous reasons, including: (1) the availability of multiple molecularly targeted agents with distinct toxicities or mechanisms of action; (2) the fact that responses to molecularly targeted agents in RCC are typically neither complete nor durable; therefore treatment with these agents must be thought of as noncurative except in rare circumstances; and (3) the fact that combination regimens of available therapies have not demonstrated substantially improved efficacy. Therefore, the goal for the practitioner treating patients with advanced RCC must be to administer these agents sequentially so as to maximize duration of disease control and quality of life for individual patients.

Perhaps the first question a practitioner should address when faced with an untreated patient with advanced clear cell RCC is whether or not the patient is a candidate for immune therapy. Although the idea of sequential therapy is based upon the assumption that advanced RCC is incurable, it should be remembered that a subset of patients can experience durable remissions from immune therapy. In the current era, immune therapy with high-dose (HD) interleukin-2 (IL-2) is still frequently given to patients with RCC at specialized centers. While IL-2 has historically been felt to benefit only a small subset of patients, recent studies suggest that in the modern era response to HD IL-2 exceeds 25%, with approximately 8% to 10% of patients exhibiting complete responses that last for more than 2 years, although efforts to identify predictive biomarkers have not yet been successful.

These improved results are most likely the result of limiting consideration of HD IL-2 to patients with certain characteristics, such as younger age, good performance status, few medical comorbidities, clear cell tumor histology, and disease that is not rapidly growing.

With respect to sequence, several clinical trials have shown that molecularly targeted therapies, both those targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), have substantial activity in cytokine-refractory patients.

 At the same time, a small retrospective study has suggested that the efficacy of HD IL-2 following VEGF—targeted therapies may be limited.

 While the latter point must be proven prospectively, these data support the premise that HD IL-2 should be considered a primary therapy for appropriately selected patients with advanced RCC.

While first-line treatment with immune therapy outside of a clinical trial is currently limited to HD IL-2, the early clinical activity reported with PD-1 and PD-L1 antibodies suggests that this might change in the near future.

 These novel immunotherapies have shown activity in multiple clinical scenarios, however, so their eventual place in sequential therapy regimens remains unclear at present. Moreover, the durability of responses to these novel agents has yet to be fully characterized. Nonetheless, the fact that treatment with VEGF- or mTOR-targeted agents so infrequently results in durable or complete remissions supports the approach that a regimen containing an immune therapy should at least be considered first line in all patients with clear cell RCC.

Once it is determined that a patient is not a candidate for immune therapy, the practitioner must select from several different FDA-approved agents characterized by 2 broad classes: (1) VEGF-targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab [plus interferon-alfa (IFN)]); and (2) mTOR inhibitors (temsirolimus) (Figure 1). Two other agents, the VEGF-targeted tyrosine kinase inhibitor (TKI) axitinib and the mTOR inhibitor everolimus, are approved only following failure of at least 1 prior therapy. The practitioner’s next decision point is affected by the assessment of the patient’s prognosis. Currently, the National Comprehensive Cancer Network (NCCN) gives a category 1 recommendation to sunitinib, pazopanib, and bevacizumab/interferon, along with a category 2A recommendation to sorafenib, for the first-line treatment of patients with predominantly clear cell advanced RCC.

Temsirolimus is also given a category 1 recommendation for the treatment with poor prognosis (defined as 3 or more of 6 poor prognostic risk factors) patients with predominantly clear cell RCC. The risk factors used by the phase III trial of temsirolimus in RCC were largely based on the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Those criteria used 6 poor-risk prognostic factors (less than 1 year from diagnosis to the start of systemic therapy, Karnofsky performance status score of 60-70, hemoglobin level less than the lower limit of normal [LLN], corrected calcium greater than 10mg/dL, LDH >1.5 times the upper limit of normal [ULN], and metastasis to greater than 1 organ site) to define patients with poor prognosis.

 Thus, temsirolimus should be considered as a first-line agent in patients with poor- risk RCC.

At the same time, while VEGF-targeted agents have not been assessed exclusively in patients with poor prognostic features, it is clear that they have activity in this group of patients. Data supporting the efficacy of sunitib in this group of patients come from the phase III trial of sunitinib versus IFN in treatment-naïve RCC patients, the sunitinib expanded access program, and retrospective analysis.

 The largest analysis arises from the expanded access program (n = 373) in which patients in the MSKCC poor-risk group had a median progression-free survival (PFS) of 4.1 months (95% CI, 3.1-5.0) and median overall survival of 5.4 months (95% CI, 4.6-6.4).

 While similar data do not yet exist for pazopanib, a randomized phase II trial of pazopanib versus temsirolimus in patients with poor-risk RCC (NCT01392183) may provide some prospective and comparative data for this subset of patients. For now, VEGFR-targeted TKIs such as sunitinib should be considered alternative first-line therapies for patients with poor-risk RCC. For most remaining patients with clear cell RCC who do not meet poor-risk criteria, the data support the use of VEGF-targeted therapy in the first line.

The most compelling data likely come from the recently reported RECORD-3 trial, a randomized phase II trial comparing the sequence of sunitinib followed by everolimus to the sequence of everolimus followed by sunitinib with the primary objective of noninferiority of everolimus compared with sunitinib in the first line. The trial failed to meet its primary endpoint with the first-line PFS of patients treated with everolimus (n = 238) of 7.9 months versus 10.7 months for patients treated with sunitinib (HR 1.4; 95% CI, 1.2-1.8).16 In the US, most patients will likely be treated with sunitinib or pazopanib, which are both TKIs with activity against VEGF receptor 2 (VEGFR2) and platelet-derived growth factor receptor (PDGFR). While both agents carry level 1 recommendations from the NCCN, comparative data have recently been made available by the COMPARZ trial.17 In this randomized, phase III, noninferiority trial, 1110 patients with clear cell RCC were randomized in a 1:1 ratio to receive either pazopanib or sunitinib at standard dose and schedule with a primary endpoint of PFS. The median PFS of patients treated with pazopanib was 8.4 months versus 9.5 months in patients treated with sunitinib.

Pazopanib was determined to be non-inferior to sunitinib with a point estimate for the hazard ratio of disease progression or death from any cause of 1.05 (95% CI, 0.90-1.22). Patients treated with sunitinib experienced a higher incidence of fatigue (63% vs 55%), hand-foot syndrome (50% vs 23%), and thrombocytopenia (78% vs 41%) compared with patients treated with pazopanib. Patients treated with pazopanib experienced a higher incidence of alanine aminotransferase elevations (60% vs 43%) compared with patients treated with sunitinib. The appended quality of life analysis revealed that patients treated with pazopanib reported less fatigue, fewer side effects, and greater satisfaction with treatment compared with patients with sunitinib. These data are supported by the results of the PISCES study, in which 169 patients with advanced RCC were randomized to receive either sunitinib followed by pazopanib or the reverse sequence with the primary endpoint of patient preference for sunitinib or pazopanib. The final analysis revealed that significantly more patients preferred pazopanib as compared with sunitinib (71% vs 22%; P <.001) with similar results for physicians (61% vs 21%).18

While this comparative data are helpful, the most reasonable approach for practitioners is to base their treatment choice on their own prior experience and on patient characteristics. For example, practitioners might favor sunitinib for patients with underlying liver dysfunction and good baseline performance status and favor pazopanib for patients with baseline fatigue or cytopenias. Ultimately, the decision for first-line molecularly targeted agents will likely be based as much on individual practitioner preference (eg, comfort and familiarity with drug dosing and side effect management, mode of administration) as on any treatment algorithms.

The NCCN guidelines also give a category 1 recommendation to the combination of bevacizumab and interferon-a based on the results of 2 independent, randomized, phase III trials comparing the combination to interferon-a alone.

 The approval of bevacizumab in combination of interferon-a has likely limited the popularity and use of this regimen in the US. However, the available data support this combination as a viable alternative to either VEGF-targeted TKI (sunitinib or pazopanib) in the first-line space.

While clear cell RCC remains by far the most common histologic subtype of RCC, accounting for 75% to 80% of renal tumors, the treatment for the other histologic subtypes, including papillary (10% to 15%), chromophobe (4% to 5%), collecting duct, medullary, Xp11.2 translocation, and unclassified (4% to 5%), remains a challenge for the field.21 Retrospective data suggest that responses to HD IL-2 in patients with non—clear RCC are extremely rare and this therapy is typically not considered in patients with non–clear cell RCC

 Most clinical trials with novel immunotherapy agents have generally excluded patients with non—clear cell histology, so the efficacy of these agents in other histologic subtypes remains largely unexplored. There also is little data on the molecularly targeted agents, although retrospective analysis suggests that in general patients with non–clear cell RCC treated with these agents experience significantly lower response rates and poorer median PF and overall survival.

Of the molecularly targeted agents, only temsirolimus has been studied in a randomized, phase III trial that accepted patients with non—clear cell histology. Upon subanalysis of this trial, among the 73 patients with non–clear cell histology (75% of which had the papillary subtype) randomized to receive either temsirolimus (n = 36) or IFN (n = 37), the median overall survival of patients was 11.6 months in the temsirolimus group versus 4.3 months in the IFN group.

For this reason, the NCCN gives temsirolimus a category 1 recommendation for the treatment of patients with non—clear cell RCC who are poor risk and a category 2A recommendation for all others.

Similarly, scant data are available for the other molecularly targeted agents. Sorafenib and sunitinib have both demonstrated modest efficacy and safety in patients with non—clear cell histology in their respective expanded-access programs and based on these data are given category 2A recommendations by the NCCN.14,26 In particular, in its expanded-access program, sunitinib showed an objective response rate of 11% and median PFS of 7.8 months (95% CI, 6.3-8.3) in 588 evaluable patients with non–clear cell histology. Sorafenib demonstrated an objective response rate of 3.1% in 127 patients with either chromophobe or papillary histology. Several clinical trials are ongoing in the patients with non–clear cell RCC.

Potentially the most informative data may be from several randomized, phase II trials comparing mTOR inhibitors with VEGF antagonists. The most recently reported of these is the ESPN study, a randomized, phase II trial in which 108 patients with non—clear cell RCC were planned to be randomized to receive either everolimus to sunitinib with planned crossover at first progression.27 At the first interim analysis, 35 patients had received everolimus and 33 patients had received sunitinib. The median first-line PFS of sunitinib was 6.1 months (95% CI 4.7-10.8) versus 4.1 months (95% CI, 2.7-7.4) with everolimus (P = .25). The median overall survival of patients treated with everolimus was 10.5 months (95% CI, 7.4-NA) while the median overall survival of patients treated with sunitinib was not reached (P = .01). Based on a futility analysis, the trial was halted and concluded that everolimus could not be recommended for the first-line therapy of patients with non–clear cell RCC.

Thus, the ideal first-line therapy for patients with non—clear RCC remains murky. Several ongoing clinical trials may add some clarity or potentially add additional therapeutic options (NCT01399918, NCT01767636). In the meantime, it appears reasonable for practitioners to treat patients with metastatic non–clear cell RCC in the first-line with either a VEGF antagonist such as sunitinib or temsirolimus.

Because only a minor subset of patients with metastatic RCC experiences durable long-term remissions from any therapy, the vast majority of patients will require a second-line therapy. Not surprisingly, the selection of a second-line therapy is greatly influenced by the identity of the first-line therapy. Patients who were treated first-line with HD IL-2 can be treated much like first-line patients, with the remaining molecularly targeted agents have shown significant activity in cytokine-refractory patients. In addition, axitinib has been given a category 1 recommendation by the NCCN following the failure of 1 prior therapy and is an option for these patients. For those patients who were treated first line with temsirolimus, a VEGF-targeted therapy such as sunitinib, pazopanib, and axitinib would be a reasonable second-line agent.

The decision is perhaps less clear cut for patients who have failed a VEGF-targeted treatment in the first line. The NCCN gives category 1 recommendations for 2 agents, everolimus and axitinib, for patients who have previously been treated with VEGF-targeted TKI. This is made even more complicated by the fact that retrospective analysis has suggested that there is no definitive cross-resistance between agents such as sorafenib, sunitinib, and bevacizumab/interferon and these agents also remain therapeutic options following initial TKI failure.28 Regardless, in principle the decision facing physicians with respect to a second-line therapy following failure of a first-line TKI is whether to prescribe another VEGF-targeted agent (axitinib or similar agent) or change to an mTOR inhibitor (everolimus). Some guidance on this decision is available from current data. First, the final analysis of the pivotal phase III trial of everolimus versus placebo (RECORD-1) suggests that everolimus has similar activity following the failure of 2 VEGF-targeted TKIs as after 1.29 At the same time, both retrospective analysis and prospective clinical trials suggest that VEGF-targeted agents may have activity following disease progression on other VEGF (or even the same) pathway inhibitors.

Finally, the only comparative trial between VEGF-targeted TKI and mTOR inhibitors was the recently reported INTORSECT trial in which 512 patients with advanced RCC who had failed prior sunitinib therapy were randomized to receive either temsirolimus or sorafenib. This phase III trial showed that there was no significant difference between temsirolimus and sorafenib in median PFS (4.3 vs 3.9 months; HR, 0.87; P = .19) or overall response rate (ORR).

However, patients treated with sorafenib experienced significantly longer overall survival compared with those treated with temsirolimus (16.6 vs 12.3 months; HR, 1.31, P = .01). Taken together, these data appear to favor the sequence of VEGF-VEGF-mTOR over VEGF-mTOR-VEGF (where VEGF indicates VEGF-targeted therapy and mTOR indicates mTOR inhibitors).

While the existing data support a certain sequence of therapies in general, the choice of second-line therapy for individual patients should take into account patient-specific factors. For example, a patient who experienced severe mechanism-specific toxicities from a VEGF-targeted agent (eg, hypertension, proteinuria, cardiac complications, etc) might benefit from changing to an mTOR inhibitor given the largely non-overlapping toxicities of these 2 classes of agents.

A patient’s clinical response to an initial VEGF-targeted therapy may also be taken into account. In a patient who is primarily refractory to a VEGF-targeted TKI, it would seem logical to try an agent with a different mechanism of action such as an mTOR inhibitor. Likewise, a patient who had a prolonged benefit from a first VEGF-targeted TKI might be more likely to benefit from a different VEGF-targeted agent. In a recently reported secondary endpoint analysis of the phase III AXIS trial, it was suggested that patients who experienced a longer PFS on first-line sunitinib tended to have a longer PFS on either axitinib or sorafenib.

 While these findings may simply reflect the underlying aggressiveness of disease, and in fact similar analysis has shown conflicting findings

 it nonetheless may be predictive of expected clinical benefit of second-line VEGF-targeted treatment.

Much like with first-line therapy, there are even less data for the sequential therapy of non—clear cell RCC. Most patients with non–clear cell RCC will be treated in the first-line setting with either a VEGF-targeted agent or an mTOR inhibitor. Given the lack of data regarding cross-resistance to the various classes of agents in patients with non–clear cell RCC, it is logical in the second-line to switch to an alternate mechanism of action. Therefore, it would be reasonable in patients who had been treated in the first-line with a VEGF-targeted therapy to proceed with an mTOR inhibitor in the second line, and vice versa. Finally, given the poor clinical outcomes observed with either available class of agent in non–clear cell RCC, it is also reasonable to seek out clinical trial options for these patients. One trial of interest is a phase II trial of axitinib in patients who have failed temsirolimus (NCT01798446).

Many novel therapeutic agents are being actively assessed in patients with advanced RCC. Although current therapy in RCC is largely limited to 2 classes of agents (VEGF-targeted agents and mTOR inhibitors), clinicians may soon be faced with the challenge of integrating agents with completely novel mechanisms of action into their therapeutic algorithms. While some agents may be combined with VEGF-targeted TKI (eg, ALK inhibitors, MET inhibitors) and others used in place of current therapies (novel PI3-kinase/mTOR inhibitors in place of the rapalogues), perhaps the most relevant class of agents with respect to sequential therapy is the novel immunotherapies given their distinct mechanism of action and efficacy in multiple clinical settings. In particular, the PD-1 antibodies are likely the closest to possibly gaining broad approval, although it should be stressed that most available data remain preliminary thus far. In addition to several combination studies (including with VEGF-targeted TKI and ipilimumab), the PD-1 antibody nivolumab is being assessed in a phase III clinical trial versus everolimus in patients with advanced RCC who have failed prior anti-angiogenic therapy (NCT01668784). A positive trial and possible approval of this agent in the second-line setting would be anticipated to have a major effect on sequential algorithms. Should PD-1 (or PD-L1) antibodies demonstrate the ability to induce durable remissions in even a subset of patients, there will be compelling rationale to move these agents into the first-line setting, either as single agents or in combination with other agents. In that case, the most appropriate sequence in most patients with clear cell RCC might become immune therapy (with PD-1/PD-L1 antibodies or HD IL-2) followed by sequential molecularly targeted therapy.

Until a therapeutic strategy emerges that can result in durable remissions for most patients with advanced RCC, sequential therapy remains a reality for most patients. For now, in the absence of data from large randomized trials, the decision on sequence of therapies must be individualized mostly based on clinical factors. These decisions will likely become increasingly complicated in the near future by the availability of novel classes of agents with distinct toxicities and mechanisms of action. However, practitioners may also soon be aided by the development of selection algorithms that are based more on genetic characterization than on clinical factors.

Affiliations: Daniel C. Cho, MD, is an assistant professor, department of medicine, Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, NY.

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February 2015 | Contemporary Oncology®

Will Immuno-oncology Become the Backbone of Treatment for all Cancers?

Update on the Management of Pain in Patients With Advanced Cancer

Sequencing VEGFR-Targeted and mTOR-Targeted Therapy in Advanced Renal Cell Carcinoma

JAK2 Mutations and JAK Inhibitors in the Management of Myeloproliferative Neoplasms

Potential Applications of Immune Checkpoint Blockade for Mesothelioma