Primary melanomas can arise from melanocytes residing within the eye (uveal melanoma), on the surface of the eye (conjunctival melanoma), within the epidermis of the eyelids (a form of cutaneous melanoma), and rarely in the eye socket (orbital melanoma). Despite their close anatomic proximity, these melanomas have very little in common aside from their shared ancestry from neural crest–derived melanocytes. Because their clinical behavior, management, prognosis, tumor node metastasis (TNM) classification schemes, and molecular characteristics differ markedly, these neoplasms are better thought of as distinct forms of melanoma, rather than being grouped together as “ocular melanoma.”

Uveal melanoma arises from the iris, ciliary body, or choroid of the eye, and it is very aggressive and resistant to therapy once metastasis has occurred. In contrast to cutaneous melanoma, a link between uveal melanoma and ultraviolet light exposure is tenuous at best.[1] Primary uveal melanoma is usually treated by high-dose localized radiotherapy (delivered by brachytherapy or charged-particle therapy) or enucleation (eye removal). Primary uveal melanoma demonstrates a strong propensity for liver metastasis in up to half of patients, and it almost never metastasizes to regional lymphatics in the head and neck.

Uveal melanoma is associated with several characteristic chromosomal gains and losses, and it frequently harbors driver mutations in several genes: 

. These genes are rarely mutated in other forms of melanoma. Likewise, genes that are frequently mutated in other forms of melanoma, such as 

 are rarely mutated in uveal melanoma. Indeed, the finding of 

 mutations has been used clinically as a means of determining the likely primary site in patients with melanoma of unknown origin. Uveal melanoma is notable for a distinctive and prognostically significant gene expression profile that has been prospectively validated for clinical use in a multicenter study.[2] Uveal melanomas with the Class 1 signature have a low metastatic risk, whereas those with the Class 2 signature have a high metastatic risk. This classification scheme is widely used to stratify patients for clinical trial entry and metastatic surveillance. Although Blum et al focus on targeted therapies based on mutations in 

 in their review,[3] these mutations are early and possibly initiating events in uveal melanoma. Thus, it is unlikely that pharmacologic modulation of these mutations alone will be sufficient to achieve durable efficacy, as has been the case with BRAF inhibitors in cutaneous melanoma. Inactivating mutations in 

 occur later in tumorigenesis, are strongly associated with metastasis, and cause uveal melanoma cells to undergo a stem cell–like phenotypic reversion that may render them more resistant to therapy.[4] Thus, it is possible that the biochemical and physiologic effects of 

 mutations must also be addressed to achieve optimal therapeutic efficacy. Histone deacetylase inhibitors and EZH2 inhibitors have shown promise in reversing the epigenetic alterations that occur with loss of 

, and these compounds require further investigation in clinical trials.[5,6]

In contrast to uveal melanoma, conjunctival melanoma is a form of mucosal melanoma, and primary conjunctival melanoma is most commonly treated by local surgical excision. Conjunctival melanoma can metastasize hematogenously, but it can also undergo regional lymphatic dissemination, which is another characteristic that distinguishes it from uveal melanoma. Although controversial, sentinel lymph node biopsy has been proposed as part of the management of conjunctival melanoma, whereas this procedure has no role in uveal melanoma. Little is known about the molecular genetics of conjunctival melanoma, except that 

Eyelid melanoma is a form of cutaneous melanoma. Consequently, eyelid melanoma is strongly linked to UV light exposure, and can display regional lymphatic spread as well as hematogenous metastasis. Eyelid melanoma is usually treated by local surgical excision, sometimes requiring extensive oculoplastic reconstructive surgery. Very little is known about the molecular genetics of eyelid melanoma aside from what is known about cutaneous melanoma in general.

Most orbital melanoma is secondary to invasion of the orbit by uveal or conjunctival melanoma, or metastasis to the orbit from a primary melanoma arising elsewhere in the body. True primary orbital melanoma is extraordinarily rare and poorly characterized.

While melanomas arising in and around the eye are relatively rare compared with cutaneous melanoma, they represent a microcosm of the various forms of melanomas that occur in humans. Eyelid melanoma and conjunctival melanoma are typical of the epithelium-associated cutaneous and mucosal subtypes, respectively, whereas uveal melanoma is representative of the non–epithelium-associated subtype.[7] There has been rapid progress in the treatment of metastasis associated with cutaneous melanoma, including impressive results achieved with targeted molecular therapies and immunotherapies, and it is possible (but still unproven) that patients with metastasis from conjunctival and eyelid melanomas may benefit from these new therapies. Although there are still no effective therapies for metastatic uveal melanoma, there has been significant recent progress in our understanding of the genetics and pathobiology of this entity. Promising new therapeutic strategies are slowly making their way into clinical trials.

Dr. Harbour is the inventor of intellectual property mentioned in the commentary and receives royalties from its commercialization. He is a paid consultant for Castle Biosciences, licensee of intellectual property presented in the commentary. 

 Singh AD, Rennie IG, Seregard S, et al. Sunlight exposure and pathogenesis of uveal melanoma. Surv Ophthalmol. 2004;49:419-28.

 Onken MD, Worley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119:1596-603.

 Blum ES, Yang J, Komatsubara KM, Carvajal RD. Clinical management of uveal and conjunctival melanoma. Oncology (Williston Park). 2016;30:29-32, 34-43, 48.

 Matatall KA, Agapova OA, Onken MD, et al. BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma. BMC Cancer. 2013;13:371.

 Landreville S, Agapova OA, Matatall KA, et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18:408-16.

 LaFave LM, Beguelin W, Koche R, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21:1344-9.

 Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239-71.

Articles

There has been rapid progress in the treatment of metastasis associated with cutaneous melanoma, including impressive results achieved with targeted molecular therapies and immunotherapies, and it is possible (but still unproven) that patients with metastasis from conjunctival and eyelid melanomas may benefit from these new therapies. 

Uveal and Conjunctival Melanoma: Close Together-but Only Distantly Related

Advanced gastrointestinal malignancies are a major oncologic challenge for which successful durable personalized therapies are currently lacking. In this issue of ONCOLOGY, Drs. Khalil and Segal provide a snapshot of the rapidly developing landscape of immunotherapy as it applies to gastrointestinal malignancies.[1] In contrast to other solid tumors, gastrointestinal malignancies have not lent themselves to immune checkpoint blockades (ICBs) and are considered to be poorly immunogenic.[2-4] However, increasing evidence suggests that a significant proportion of distinct gastrointestinal malignancy subtypes, including microsatellite-instable colorectal cancer and hepatocellular carcinoma (HCC), will benefit from ICBs.[5,6]

The key questions currently facing the field are: (1) Which gastrointestinal malignancies are sensitive to which ICBs? (2) Among the gastrointestinal subtypes, which biomarkers predict response? (3) Why are some gastrointestinal tumor subtypes less amenable to immunotherapy? (4) Which combination therapy will result in a response?

Answers to these questions will help us understand the fundamental biology of immune response and evasion, and will aid in designing meaningful treatments, including selection of the right combinations for sustained responses.

Variable successes amongst tumor types have identified important but not definitive predictive biomarkers of responses to ICBs that currently include tumor mutation burden,[7,8] baseline programmed death ligand 1 (PD-L1) expression, and number of tumor-infiltrating lymphocytes (TILs).[9] Response to ICBs will be determined by the tumor milieu, which is comprised of neoplastic cells, tumor microenvironment, local immune system, and the complex interplay between them. Neoplastic cells use various mechanisms to escape recognition by the immune system, including expression of checkpoint ligands such as PD-L1, downregulation of major histocompatibility complex class I expression, and overexpression of C-X-C chemokine receptor type 4 (CXCR4).[10] Elements within the tumor stroma interact with the neoplastic cells and cooperate to support tumor growth, migration, and invasion. Cancer-associated fibroblasts (CAFs) within the pancreas tumor stroma are activated by neoplastic cells and in turn release tumor-promoting factors, including CXC ligand 12 (CXCL12), which results in cultivating a local immunosuppressive environment.[11]

Tumor Stroma and Infiltrating Lymphocytes

Distinct early-phase trials testing ipilimumab and durvalumab in advanced pancreatic cancer have resulted in limited transient responses.[12,13] Why do ICBs not result in a substantial response in pancreatic cancer? And if they rarely occur, why are the responses not durable? It is likely the result of a highly immunosuppressive tumor microenvironment, which ICBs are unable to overcome; therefore, a potent combination approach is needed for immunotherapy to have a chance. Similar to results in humans, antibodies to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) or PD-L1 alone failed to control tumor growth in KPC mice (LSL-K-ras

/+; Pdx-Cre), a well-established genetically engineered mouse model of pancreas adenocarcinoma.[11] However, when fibroblast-associated, protein-expressing CAFs were conditionally depleted within these animals, or CXCL12 was negated by inhibiting its receptor CXCR4 with a small molecule, KPC mice treated with anti–PD-L1 experienced slight tumor shrinkage (~15%) in short-term experiments. Tumors from mice treated for 24 hours with this combination resulted in an increased accumulation of T cells within the tumor.[11] These preclinical studies show promising results, but key questions remain:

• The small response was observed within 2 days of treatment, which is in contrast to a delay in response observed in patients treated with ICBs. Does this early stabilization/response truly reflect the immune-mediated response observed in other tumors?

• In long-term studies, will tumor response be enhanced and durable, and result in a survival benefit?

CXCessoR4 (Clinicaltrials.gov identifier: NCT02472977) is a phase I/II study testing this combination with ulocuplumab (anti-CXCR4) and nivolumab (anti–PD-1) in solid tumors. Although combination ICB and anticytokine therapy hold promise, the highly immunosuppressive environment in pancreatic cancer in combination with the high tumor burden in metastatic disease may be a high bar to reach to yield sustained responses. Although speculative, this combination is likely to benefit patients in the adjuvant setting where the tumor microenvironment may not have fully matured in order to reconstitute the immunosuppressive environment with the same vigor. Addition of radiation or chemotherapy to ICBs along with this combination therapy may enhance antineoplastic effect in pancreatic cancer, as has been observed in other malignancies.[14] CXCR4 and CXCL12 represent only one axis in a complex network of interactions that the tumor manipulates to evade the immune system.[15]

Increased tumor mutation burden and neoantigen expression is associated with an increased likelihood of durable response to ICBs.[7,8] It is thought that the antitumor response already exists but is exhausted, and ICBs merely reactivate them. Mismatch repair–deficient (microsatellite-instable [MSI]) colorectal cancers have a 10- to 100-fold increase in somatic mutations compared with mismatch repair–proficient (microsatellite-stable [MSS]) colorectal cancers, which results in an increased number of mutation-associated neoantigens.[16] MSI colorectal cancer patients experienced overall survival benefit compared with their MSS counterparts.[5] A high proportion of the MSI patients had hereditary nonpolyposis colorectal cancer, and although it is unlikely that patients with sporadic mismatch repair deficiency would respond differently, this fact needs to be demonstrated in a clinical trial setting and holds great promise for this small population of colorectal cancer patients.

PD-L1 is constitutively expressed in HCC tumor cells both in vitro and in vivo. Nivolumab, a PD-1 inhibitor, demonstrated activity in patients with advanced HCC who had progressed on sorafenib. Interim results presented at the 2015 American Society of Clinical Oncology Annual Meeting demonstrated a 23% objective response rate, which included two complete responses and six durable partial responses among 39 patients.[5] The overall survival was 62% at 12 months compared with the median overall survival of 8 months after sorafenib failure.[5,17] In preclinical studies, PD-L1–positive HCC tumor cells induce apoptosis within T cells, rendering them ineffective, and PD-L1–blocking antibodies inhibit this tumor-induced T-cell death.[18] PD-L1 expression, TILs, and regulatory T cells play a prognostic role in both survival and recurrence.[19,20] We propose ICBs to be used in concert with ablative therapies to increase the number of transplant-ineligible localized HCC patients toward eligibility for a curative liver transplant. This combination will also likely reduce wait-list dropout rates, resulting in more patients receiving a liver transplant. The safety and timing of individual therapies in this setting and its effect on transplant needs to be demonstrated in early-phase trials.

The previous examples demonstrate the benefit of intervening in only a few of the many immune evasion mechanisms and are likely a prelude to future benefits. The challenge will be to identify the key regulators of the immune evasion mechanisms specific to tumor subtypes. These studies, including inhibiting new checkpoints (lymphocyte-activation gene 3, indoleamine 2,3-dioxygenase, and others) and combinations, are currently underway.

Dr. Manji receives research funding from Conquer Cancer Foundation and Merck; he is also a consultant for Ardelyx

 Khalil DN, Segal NH. Modern immunotherapy for the treatment of advanced gastrointestinal cancers. Oncology (Williston Park). 2016;30:85-90, 93.

 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.

 Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-28.

Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.

 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.

 El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(suppl). Abstr LBA101.

 Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:1-11.

 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

 Nomi T, Masayuki S, Takahiro A, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151-7.

 Chatterjee S, Behnam AB, Nimmagadda S, et al. The intricate role of CXCR4 in cancer. Adv Cancer Res. 2014;124:31-82.

 Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013;110:20212-7.

 Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828-33.

Segal NH, Hamid O, Hwu W, et al. A phase 1 multi-arm dose-expansion study of the anti-programmed cell death ligand-1 (PD-L1) antibody MEDI4736: preliminary data. Ann Oncol. 2014;25:iv361-72.

 Victor CT, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373-7.

Wang J, Reiss KA, Khatri R, et al. Immune therapy in GI malignancies: a review. J Clin Oncol. 2015;33:1745-53.

 Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-7.

 Lee IC, Chen YT, Chao Y, et al. Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice. Medicine. 2015;94:e688.

 Muhlbauer M, Fleck M, Schutz C, et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 2006;45:520.

 Gao Q, Wang X-Y, Qiu S-J, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971.

 Wu P, Wu D, Li L, et al. PD-L1 and survival in solid tumors: a meta-analysis. PLoS One. 2015;10:e0131403.

Advanced gastrointestinal malignancies are a major oncologic challenge for which successful durable personalized therapies are currently lacking. 

Immune Targeting in Gastrointestinal Malignancies: Finding the Right Combination for the Right Site 

While colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States, both its incidence and mortality rate continue to decline.[1] These improvements are likely due to better cancer prevention/screening, earlier diagnoses, and improved treatments. Nevertheless, 20% of patients with newly diagnosed colon cancers present with metastatic disease, and 80% to 90% of these patients present with unresectable metastatic liver disease.[1,2] Cure is possible in a percentage of this patient population.[3] Drs. Al-Hajeili, Marshall, and Smaglo present a comprehensive review of the available data on preoperative or induction/conversion therapy in patients with resectable disease, as well as disease initially deemed unresectable, at diagnosis [4]; however, it remains difficult to decipher which patients are appropriate candidates for conversion therapy vs upfront surgery. Therefore, in predicting potential outcomes, several factors should be considered. Here, we will attempt to address such factors and provide insights.

Should the pattern of metastatic occurrence influence resection and/or perioperative therapy? In two-thirds of patients with metastatic colorectal cancer, metastases develop in a metachronous manner; however, up to 20% to 35% of patients present with synchronous liver metastases, which may have a worse prognosis than metastatic colorectal liver disease that develops metachronously.[2,5,6] In a retrospective series of 155 patients who had undergone liver resection for metastatic disease, those with synchronous lesions had more sites of liver involvement and more bilobar metastases than those with metachronous metastases.[6] Thus, these patients may require more careful monitoring and aggressive perioperative chemotherapy, since this type of presentation may be an indicator of disseminated disease.

Is there any use for positron emission tomography/computed tomography (PET/CT) in the evaluation of distant metastatic disease? According to the National Comprehensive Cancer Network Clinical Practice Guidelines, the radiographic workup for metastatic colon cancer includes CT scanning with intravenous contrast of the chest, abdomen, and pelvis. Magnetic resonance imaging of the abdomen and pelvis can be considered when other imaging is inadequate, to help identify hepatic metastases more clearly. Although PET/CT is not routinely recommended for staging or follow-up in colon cancer, it may be beneficial to evaluate for unrecognized metastatic disease that would impede surgery in those with potentially resectable colorectal cancer and isolated liver metastases.[7] In a randomized clinical trial by Moulton et al, the role of preoperative PET/CT was evaluated in patients with resectable metachronous liver metastases to help identify those with occult metastases and thus to avoid noncurative surgery. While PET/CT had no impact on overall survival, surgical management was altered in 8% of patients, with 2.7% of patients identified as having additional metastatic disease (bone, peritoneum/omentum, abdominal lymph nodes).[8] In addition, fluorodeoxyglucose (FDG)-PET has been shown to be superior to CT alone. In a systematic review of retrospective data, the pooled sensitivity and specificity of FDG-PET were 80% and 92%, respectively, for hepatic disease, and 91% and 98%, respectively, for extrahepatic disease. With CT alone, the pooled sensitivity and specificity for hepatic disease were 83% and 84%, respectively, and 61% and 91%, respectively, for extrahepatic metastases.[9] Therefore, the addition of PET to CT may increase the accuracy of resection.

Diagnostic laparoscopy may help identify occult intraperitoneal metastases in those with potentially resectable metastatic liver lesions; however, this modality is commonly reserved for patients thought to be at highest risk. Such patients include those with suspicion for peritoneal carcinomatosis on radiographic imaging or those with metachronous presentation of multiple liver metastases not responsive to chemotherapy. In patients with potentially resectable metastatic colon cancer, multidisciplinary evaluation is recommended, including surgical consultation with an experienced hepatic surgeon to assess resectability and potential for cure with preservation of adequate liver reserve.[7] Thus, resection should be considered only if a complete or R0 resection is possible, since incomplete resection has not been shown to be beneficial.[3,10,11] Previously, contraindications to liver resection included the presence of more than four lesions, bilobar distribution, inability to achieve a 1-cm resection margin, portal lymphadenopathy, or other extrahepatic metastases. However, with better chemotherapy and surgical strategies (ie, staged procedures), the optimal selection of resection candidates is evolving, with a focus on residual liver function and volume.[12]

As Al-Hajeili et al mention in their review, chemotherapy-related liver toxicity is a concern, both in patients with a history of liver disease and in those without, particularly with the use of preoperative irinotecan- or oxaliplatin-containing regimens. Hepatic sinusoidal abnormalities, as well as nodular regenerative hyperplasia, have been described predominantly in those patients receiving oxaliplatin before resection. Irinotecan-containing regimens are more often associated with steatosis or steatohepatitis.[13,14] With the increasing epidemic of obesity in this country, steatohepatitis has been seen more often in patients with higher body mass index.[15,16] While the data are conflicting with regard to perioperative morbidity/mortality in relation to liver damage,[13,17-19] it is important to recognize affected patients and to consider upfront resection if possible; however, there have been no randomized studies or large meta-analyses to date.

What lies in the future? Perhaps, with a greater understanding of cancer genomics, certain biomarkers may prove valuable in identifying patients who might benefit from induction/conversion therapy followed by metastasectomy, even though at this time the prognostic value of such markers is not known. A promising example may be found in recently published data by Le et al, who evaluated the clinical activity of pembrolizumab, an anti–programmed death 1 (PD-1) immune checkpoint inhibitor, in patients with progressive metastatic colorectal cancer and found that pembrolizumab had activity in the subset of patients with mismatch repair deficiency.[20] Conceivably, the combination of genomic markers and “traditional parameters” could influence or enhance clinical evaluation, guide therapy, and assist in determining the optimal sequence of therapies in the future.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.

 Muratore A, Zorzi D, Bouzari H, et al. Asymptomatic colorectal cancer with un-resectable liver metastases: immediate colorectal resection or up-front systemic chemotherapy? Ann Surg Oncol. 2007;14:766-70.

 Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol. 2006;13:1261-8.

 Al-Hajeili M, Marshall JL, Smaglo BG. Neoadjuvant treatment for surgically resectable metastatic colorectal cancer. Oncology (Williston Park). 2016;30:10-6, 28.

 Hayashi M, Inoue Y, Komeda K, et al. Clinicopathological analysis of recurrence patterns and prognostic factors for survival after hepatectomy for colorectal liver metastasis. BMC Surg. 2010;10:27.

 Tsai M-S, Su Y-H, Ho M-C, et al. Clinicopathological features and prognosis in resectable synchronous and metachronous colorectal liver metastasis. Ann Surg Oncol. 2007;14:786-94.

 Clinical Practice Guidelines in Oncology (NCCN Guidelines). Colon cancer. Version 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed December 3, 2015.

 Moulton CA, Gu CS, Law CH, et al. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA. 2014;311:1863-9.

 Wiering B, Krabbe PF, Jager GJ, et al. The impact of fluor-18-deoxyglucose-positron emission tomography in the management of colorectal liver metastases. Cancer. 2005;104:2658-70.

 Scheele J, Altendorf-Hofmann A, Grube T, et al. Resection of colorectal liver metastases. What prognostic factors determine patient selection? Chirurg. 2001;72:547-60.

 Kornprat P, Jarnagin WR, Gonen M, et al. Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol. 2007;14:1151-60.

 Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist. 2008;13:51-60.

 Pawlik TM, Olino K, Gleisner AL, et al. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg. 2007;11:860-8.

 Robinson SM, Wilson CH, Burt AD, et al. Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis. Ann Surg Oncol. 2012;19:4287-99.

 Bilchik AJ, Poston G, Curley SA, et al. Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note. J Clin Oncol. 2005;23:9073-8.

 Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005;200:845-53.

 Parikh AA, Gentner B, Wu TT, et al. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg. 2003;7:1082-8.

 Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 2008;247:118-24.

 Scoggins CR, Campbell ML, Landry CS, et al. Preoperative chemotherapy does not increase morbidity or mortality of hepatic resection for colorectal cancer metastases. Ann Surg Oncol. 2009;16:35-41.

It remains difficult to decipher which patients are appropriate candidates for conversion therapy vs upfront surgery. Therefore, in predicting potential outcomes, several factors should be considered. Here, we will attempt to address such factors and provide insights.

Neoadjuvant Treatment for Surgically Resectable Metastatic Colorectal Cancer: Is There an Optimal Succession? 

Many states have already passed Right-to-Try drug laws, which give critically ill patients the right to try medications that have not been approved by the US Food and Drug Administration (FDA). These laws have supporters and critics-and I understand you are one of the latter. Can you explain your opposition to Right-to-Try laws, specifically from an ethics perspective?

 Right-to-Try laws sound good in the abstract, but they are unethical in that they promise much, but deliver nothing. The laws give people a right to ask companies for drugs or devices that have gone through phase I testing without requiring permission from the FDA. But patients have always had the right to ask sponsors/companies for drugs or devices, and these laws do not obligate or compel companies to give anything. The laws are, unfortunately, quick-fix, feel-good political responses to a very serious, very complex problem. Since the FDA approves 99% of requests that companies present to them, the Right-to-Try laws essentially create false hope among the desperate. Tellingly, there is not a single example of anyone in a Right-to-Try state getting anything as a direct result of these laws. Nor do the laws budget any money to pay for drugs, transportation, hotels, time lost from work, or any other costs commonly associated with trying a novel drug. They are, at best, misleading in that they talk of rights but create absolutely no such thing.

 Even though the FDA Compassionate Use program is meant to facilitate the same access to unapproved drugs as the Right-to-Try laws, there have been complaints that there are too many obstacles for patients to get the drugs they want to try at the time they need them. Are the Right-to-Try laws intended to correct these problems-and if so, how successful are they at doing this?

 The FDA is not the obstacle to compassionate use. The proponents of the Right-to-Try laws demonize the FDA, but it is almost never the problem. The FDA moves quickly in response to requests and recently made the process even more efficient by streamlining its website. It is pure ideology that blames the FDA for getting in the way of compassionate use.

The main challenge is the drug sponsors and companies rather than any regulatory agency. Companies and their boards may not want to get involved early on with compassionate use. Some companies are too small to manage requests. Some fear bad publicity if someone on compassionate use dies. Some expect payment for making a drug available. Right-to-Try laws do not address any of these issues.

What advice and/or tips would you give to clinicians with terminally ill patients who have exhausted all their therapy options and are interested in trying experimental drugs? What information is crucial for them to have before moving forward?

 They need to monitor the literature to see what trials are going on and should check ClinicalTrials.gov-although that site has many problems, among them a failure to update the status of trials that may be listed as open, but actually have closed enrollment. Visit the drug company’s website, if there is one, to see what they say about compassionate use. The patient should find out the name of the chief marketing officer, and requests should be made specifically to that person.

Requests ought to include all relevant medical and social data, including a statement that any treatment alternatives have been tried or, if not, why; the reasons that the patient cannot get into a clinical trial or employee assistance program; a comment on likelihood of compliance and the practicality of administering a new drug or biologic; a promise to provide information about what happens to the patient if compassionate use is granted; and all contact info for the doctor, patient, and patient’s key family member.

Dr. Caplan serves as the non-voting Chairperson of the Compassionate Use Advisory Committee (CompAC), an external expert panel of internationally recognized medical experts, bioethicists, and patient representatives formed by NYU School of Medicine, which advises Janssen about requests for compassionate use of its investigational medicines.

In this Q&A we examine Right-to-Try drug laws and discuss tips for clinicians with terminally ill patients who have exhausted all their therapy options.

Medical Ethicist Arthur Caplan Explains Why He Opposes ‘Right-to-Try’ Laws

Oncologists have a great deal of enthusiasm for adjuvant therapy. In fact, it is one of the few places where we can actually have a curative impact on patients with solid tumors. While there have been great strides in adjuvant therapy in some diseases, such as breast cancer, our success in the setting of colorectal cancer has been more modest. In stage III disease, only 1 of every 4 patients who receive adjuvant therapy experiences significant benefit; in stage II disease, only 1 in 20 appears to benefit.

Unfortunately, we have not been able to predict, using molecular testing, which patients are at risk and which will benefit in a prospective fashion. Nor have we been willing to acknowledge (or document) that when we apply adjuvant therapy to an entire population, knowingly benefiting a small subset, we may in fact do significant harm to some patients. Our enthusiasm for curing the few outweighs our negative impact on the majority.

Over the last 20 years we have created a new clinical setting now known as “stage IV–no evidence of disease.” We all have many of these patients in our clinics. They range from patients with isolated peritoneal nodules or liver metastases that have been resected, to those with multiple metastases that have been resected and ablated. On the one hand, we are delighted that we have gotten these patients to this state; on the other hand, we know that these patients have a very high risk of persistent cancer. Because of our enthusiasm for adjuvant therapy and our belief that our new medicines will have an adjuvant-like effect on these patients, we have treated them perioperatively and postoperatively in the hope of offering additional curative benefit. However, we must recognize that there is absolutely no evidence to support doing this.

As we reflect on the history of adjuvant therapy for colorectal cancer over the past decade, it is striking that agents that have significant impact in the metastatic setting have failed in the adjuvant, curative setting. This has not been the case in other malignancies, which suggests that micrometastatic colon cancer has unique properties not seen in other cancers. Theories involving epithelial-mesenchymal transition[1] and stem cells[2] suggest that the cells we are killing in the micrometastatic setting, which yield the adjuvant effect, may not be the same cells we are treating in patients with stage IV–no evidence of disease colorectal cancer.

In clinic, I typically use the gardening analogy of “seed” and “small plant.” Our two agents with activity in the adjuvant setting, fluorouracil (5-FU) and oxaliplatin, have curative potential on seeds. But I suspect that in the patient with stage IV–no evidence of disease colorectal cancer, any residual cells we are treating are, in fact, small plants-early metastatic disease. Chemotherapy does not have curative potential in metastatic disease. Therefore, giving a set amount of chemotherapy in the hope of offering additional curative impact has little justification in science.

A major failing of the gastrointestinal research community is that we have not done adequate studies of the role of chemotherapy in this setting. But first we must recognize that these are very difficult clinical trials to design. Patients with widely variable risks would all be included, and we have no solid biomarker other than relapse to determine the impact of treatment. We have performed only a few studies, and these studies have failed to demonstrate an overall survival benefit for patients in this setting.

The European Organisation for Research and Treatment of Cancer study is the best trial we have that has examined perioperative FOLFOX (leucovorin [folinic acid], 5-FU, oxaliplatin) in patients who have undergone liver resection.[3] The results demonstrated that there was an 8% improvement in progression-free survival at 3 years; however, this was a small, underpowered study, and it failed to demonstrate an overall survival benefit. Many see this trial as justification for giving FOLFOX chemotherapy in the perioperative liver resection setting, but others-including me-see it as a negative trial. Another study looked at epidermal growth factor receptor–based therapy in the perioperative setting. Unfortunately, this study had negative results that demonstrated potential harm from the addition of biologics in this setting.[4] In both studies, logic dictated that the chemotherapy should have resulted in an improved outcome. However, neither study demonstrated this.

Clearly, what is needed is a new approach to the treatment of patients with stage IV–no evidence of disease colorectal cancer. This is an ideal opportunity for clinical trials to look at novel therapies and approaches. I believe most of these patients should be treated as if they have residual metastatic disease; with this premise, one might adopt a watch-and-wait strategy rather than a maintenance-like strategy. Repeated rounds of intensive chemotherapy with intent of cure do not seem justified based on the literature or scientific logic and therefore should not be given to these patients. The only exception is in the perioperative setting, where demonstration of clinical responsiveness or downstaging/conversion would be of use. In all other settings, giving chemotherapy just to make us feel better emotionally in exchange for potential harm to the patient is not the right strategy. We need to find better treatments for this new clinical indication.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

Bates RC, Mercurio AM. The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther. 2005;4:365-70.

 Kreso A, van Galen P, Pedley PM, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014;20:29-36.

 Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-16.

 Baker H. Cetuximab for liver metastases from colorectal cancer. Lancet Oncol. 2013;14:e204.

In all other settings, giving chemotherapy just to make us feel better emotionally in exchange for potential harm to the patient is not the right strategy. We need to find better treatments for this new clinical indication.

Adjuvant Therapy After Resection of Metastatic Colorectal Cancer: Scant Evidence of a Curative Benefit

Nearly 60% to 70% of patients will relapse within the first 2 years after resection of metastatic colorectal cancer.[1] The principle of adjuvant treatment is to eradicate residual micrometastatic disease in patients at high risk for recurrence. This concept was established 25 years ago in stage III colon cancer.[2] The current standard of care in the adjuvant management of stage III colon cancer is based on the MOSAIC study, which showed the superiority of FOLFOX (leucovorin [LV; folinic acid], fluorouracil [5-FU], oxaliplatin) over 5-FU and LV more than a decade ago.[3] Patients with resected stage IV colorectal cancer have at least the same-or, more commonly, a significantly higher-risk of tumor recurrence and death as those with stage III disease. These prognostic implications constitute the biological rationale for adjuvant therapy in patients with resected metastatic colorectal cancer.[4]

Here we will focus on the role of adjuvant therapy after resection of metastatic disease. We will not discuss the results of the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial, which confirmed the benefit of perioperative FOLFOX in terms of disease-free survival (DFS), since the study included neoadjuvant chemotherapy before metastasectomy.[5,6] Its results can, however, serve as confirmatory data for the efficacy of systemic chemotherapy in the context of resection of metastases with curative intent.

The first multicenter trial that compared systemic intravenous adjuvant chemotherapy (5-FU/LV) with surgery alone after resection of liver metastases showed a result that favored the treatment arm.[7] A total of 173 out of 200 previously planned patients were randomized over a period of 10 years. Patients in the chemotherapy group achieved a 5-year DFS of 33.5%, compared with 26.7% in the control group, with statistical significance after multivariate analysis (odds ratio [OR] for recurrence or death in the chemotherapy group, 0.66 [95% confidence interval (CI), 0.46–0.96]; 

 = .028). There was a trend toward increased 5-year overall survival (OS) for those who received adjuvant chemotherapy compared with those who had surgery alone: 51.1% vs 41.1% (OR for death in the chemotherapy group, 0.73 [95% CI, 0.48–1.10]; 

Subsequently, the EORTC/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia (ENG) trial, which had a similar design, randomized 107 patients, and again an advantage was observed for adjuvant chemotherapy with a 5-FU bolus–based regimen. The lack of a significant survival benefit in these two trials when their results were analyzed separately was thought to be due to the smaller than planned sample size, slow accrual, and premature closure in both trials. Thus, a pooled analysis of the results of these trials was conducted. This analysis-with a total of 278 patients-showed a strong trend toward a survival benefit for adjuvant chemotherapy, with borderline statistical significance. Median progression-free survival (PFS) was 27.9 months in the chemotherapy group vs 18.8 months in the surgery-alone group (hazard ratio [HR], 1.32 [95% CI, 1.00–1.76]; 

 = .058). Median OS was 62.2 months in the chemotherapy group vs 47.3 months in the surgery-alone group (HR, 1.32 [95% CI, 0.95–1.82]; 

 = .095). However, in a multivariable analysis there was a significant association in favor of adjuvant treatment for both PFS (

Several retrospective series have also shown benefit for adjuvant systemic treatment after liver resection. A large study that included two prospective databases with a total of 792 patients demonstrated that 5-FU–based chemotherapy improved survival (

 = .007), even after stratification by clinical risk score (CRS) (

 = .001). Patients treated with adjuvant chemotherapy had a 1.3 to 2.0 times higher chance of survival.[9]

Another prospective database, with 297 patients, evaluated the predictive value of a CRS along with the benefit of adjuvant therapy after resection of metastases. This analysis included patients treated with FOLFOX (53%), FOLFIRI (LV, 5-FU, irinotecan) (14%), or 5-FU/LV (33%).[10] An OS benefit for patients who received adjuvant systemic chemotherapy (HR, 0.69 [95% CI, 0.49–0.98]; 

 = .04) was found to be even more robust in the higher-risk group with CRS > 2 (HR, 0.40 [95% CI, 0.23–0.70]; 

Hepatic arterial chemotherapy infusion (HAI) has also been studied as adjuvant treatment after resection of liver metastases, either alone or combined with systemic chemotherapy. Despite the high heterogeneity concerning the protocols for HAI, its safety and efficacy have been demonstrated, particularly when HAI is combined with systemic chemotherapy.[11,12] A recent systematic review and meta-analysis that included six randomized trials, three cohort studies, and a total of 1,057 patients assessed the long-term outcomes of adjuvant HAI.[13] The review showed that patients who received adjuvant HAI, whether or not combined with systemic chemotherapy, exhibited a significantly higher 5-year OS (HR, 0.75 [95% CI, 0.56–0.99]; 

 = .048) and 5-year DFS (HR, 0.61 [95% CI, 0.48–0.79]; 

 = .001) than those who did not receive HAI. Nevertheless, the adverse events following HAI-particularly sclerosing cholangitis and complications related to HAI pumps-should be considered; thus, this modality has not achieved widespread acceptance.[14]

In conclusion, there is clear proof of principle for adjuvant therapy in patients at high risk for tumor recurrence, such as those with resected metastatic colorectal cancer. For that reason, this strategy has been largely adopted, especially using 5-FU– and oxaliplatin-based regimens, thereby mirroring the approach in resected stage III colon cancer. Therefore, we do favor systemic adjuvant therapy after resection of metastases for most patients.

Dr. Coutinho serves as a speaker for and receives honoraria from Sanofi. Dr. Grothey has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250:440-8.

 Moertel CG, Fleming TR, MacDonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352-8.

 Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.

 Power DG, Kemeny NE. Role of adjuvant therapy after resection of colorectal cancer liver metastases. J Clin Oncol. 2010;28:2300-9.

 Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208-15.

 Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006;24:4976-82.

 Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008;26:4906-11.

 Parks R, Gonen M, Kemeny N, et al. Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents. J Am Coll Surg. 2007;204:753-61.

 Rahbari NN, Reissfelder C, Schulze-Bergkamen H, et al. Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy. BMC Cancer. 2014;14:174.

 Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999;341:2039-48.

 Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med. 2005;352:734-5.

 Liu W, Song QK, Xing BC. A systematic review and meta-analysis to reappraise the role of adjuvant hepatic arterial infusion for colorectal cancer liver metastases. Int J Colorectal Dis. 2015;30:1091-102.

 Zhang W, Song T. The progress in adjuvant therapy after curative resection of liver metastasis from colorectal cancer. Drug Discov Ther. 2014;8:194-200.

There is clear proof of principle for adjuvant therapy in patients at high risk for tumor recurrence, such as those with resected metastatic colorectal cancer. For that reason, this strategy has been largely adopted, especially using 5-FU– and oxaliplatin-based regimens, thereby mirroring the approach in resected stage III colon cancer.

Adjuvant Therapy After Resection of Metastatic Colorectal Cancer: Clear Proof of Principle in This Setting

Breakthrough successes within the last 5 years have brought immunotherapy to the forefront of cancer therapy.[1,2] The development of immune checkpoint inhibition, which targets T-cell regulatory pathways and enhances antitumor immune responses by reversing T-cell exhaustion, has led to important clinical advances in the treatment of melanoma, lung cancer, and renal cell cancer.[2] Consistent with this, Bourla and Zamarin have described modulation of the host immune response to tumors, which is now recognized as an exciting new therapeutic target in gynecologic malignancies.[3] The major challenges to this strategy include the limited activity of single-agent immunotherapy and the lack of reliable biomarkers to predict patient response. The clinical evaluation of immunotherapy has focused on single agents to date.[1] The single-agent activity of immune checkpoint inhibitors in recurrent ovarian cancers is associated with objective response rates of approximately 15%.[4] Hence, it may be necessary to target other pathways to augment the checkpoint blockade and to address the dynamic events underlying the host immune response.[5]

Active therapeutic targets in recurrent ovarian cancer include DNA damage repair and vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) signaling pathways. Emerging data indicate that the VEGF and VEGFR pathways modulate immune response by increasing DNA damage and tumor mutational loads.[6,7] Mutational load, leading to increased potential neoantigen expression, has been associated with clinical response to immune checkpoint inhibitors in colorectal cancer and melanoma.[8,9] Approximately 50% of high-grade epithelial ovarian cancers have acquired or inherited dysfunction in homologous recombination, high-fidelity DNA double-strand break repair.[10] All high-grade epithelial ovarian cancers have genomic instability that is partially associated with loss of normal p53 function.[6]

Poly (ADP-ribose) polymerase (PARP) 1 has many roles in DNA damage repair, including repair of single-strand DNA breaks via the base excision repair pathway.[11] Preclinical studies have shown that PARP inhibitors promote local antigen release, resulting in systemic antitumor response after tumor exposure to radiation or DNA-damaging agents or secondary to spontaneous or heritable defects in DNA.[5,12] Increased DNA damage resulting from PARP inhibitors or exposure to other DNA-repair inhibitors would thus yield greater mutational burden and expand the neoantigen microenvironment.[13]

PARP inhibitors are also associated with immunomodulation. Huang et al reported that talazoparib (BMN 673) increased the number of peritoneal CD8+ T cells and natural killer cells, and increased production of interferon Î³ and tumor necrosis factor Î± in a 

-mutated ovarian cancer xenograft model.[14] These data suggest that PARP inhibitors may be complementary to immune checkpoint modulation in yielding clinical benefit in recurrent ovarian cancer. Currently a phase I/II study of the programmed death (PD) ligand 1 (PD-L1) inhibitor MEDI4736 (durvalumab) in combination with olaparib is being conducted in patients with solid tumors and recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT02484404).

Angiogenesis pathways interact with both immune response and DNA repair mechanisms. Tumor hypoxia induces downregulation and decreased expression of genes and proteins involved in DNA damage repair, leading to further DNA damage, genomic instability, and cell death.[15-17] VEGF has been shown to reduce the antitumor immune response in preclinical and clinical models, including suppression of dendritic cell maturation, inhibition of T-cell responses, and an increase in regulatory T cell proliferation and accumulation of myeloid-derived suppressor cells (MDSCs).[18-21] In addition, PD-L1 expression was upregulated under hypoxic conditions in a panel of mouse and human tumor cell lines,[22] as well as in splenic MDSCs,[23] through a hypoxia-inducible factor-1Î±–dependent mechanism. Angiogenesis inhibitors are active in gynecologic cancers; bevacizumab[24,25] and the oral VEGFR1-3 tyrosine kinase inhibitor cediranib[26,27] have been associated with improved progression-free survival. Thus, angiogenesis inhibition may lead to increased mutational load and potential neoantigens, and may promote an antitumor immune response. Ongoing and new clinical trials will investigate this hypothesis in gynecologic cancers.

It is crucial to identify biomarkers that can predict the response to immunotherapies, particularly with the new checkpoint blockade agents. The overexpression of PD-L1 is an important and widely explored biomarker for response to immune checkpoint inhibitors.[28] However, PD-L1 expression as demonstrated by immunohistochemistry fails to accurately select all patients who are suitable for PD-1/PD-L1 pathway blockade. A phase II study in patients with ovarian cancer recently reported by Hamanishi et al indicated that the expression of PD-L1 did not significantly correlate with objective response.[4] Primary tumor samples may not represent the dynamic processes present in the immune milieu in recurrent disease. The expression of PD-L1 may be altered by prior treatment or by inflammatory changes at tumor sites. Optimization and harmonization of diagnostic and fit-for-purpose assays and examination of parallel and related pathways are needed to better guide patient selection and therapeutic choices.

Tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment, and their characterization by PD-L1 and expression of other immune biomarkers, may be important in predicting the clinical benefit of checkpoint blockade.[28,29] The clinical benefit of immune checkpoint inhibition is seen when immunogenic tumors and tumors with increased neoantigen production are treated with these inhibitors.[4]

Tumors with DNA damage repair deficiencies are recognized to have high(er) mutational loads, and thus potentially to express more neoantigens.[6,30] Suppressor (CD8+) and helper (CD4+) T cells recognize mutated peptides resulting from tumor-specific DNA mutations; neoantigen-specific T-cell responses have been associated positively with clinical response to immune checkpoint inhibition.[9] Le et al reported that administration of the PD-1 inhibitor nivolumab resulted in a higher response rate in mismatch repair (MMR)-deficient colorectal cancer compared with MMR-proficient colorectal cancer (40% vs 0%, respectively).[8] The high numbers of somatic mutations and neoantigens in MMR-deficient colorectal cancer correlated with longer progression-free survival.

Howitt et al also reported that polymerase Îµ–mutated and microsatellite-instable (MSI) endometrial cancers are associated with high neoantigen loads and numbers of TILs, which is counterbalanced by overexpression of PD-1 and PD-L1.[31] Patch et al recently showed that germline 

 mutation–associated ovarian cancer has a higher mutational load and quantity of neoantigens compared with 

 wild-type ovarian cancer.[6] Patients with these types of ovarian or endometrial cancer may be particularly suited for therapy with PD-1/PD-L1 inhibition.

The advent of immunotherapy presents us with new treatment approaches in gynecologic cancers, with preliminarily promising outcomes. Multiple clinical trials are currently being conducted to better define the role of immunotherapy. Further investigation is warranted to develop and identify predictive biomarkers. Determining the optimal timing or sequencing of immune-modulatory interventions will also be important, given the crucial role of the dynamics of immune reactions; this may require novel or adaptive trial designs. Assessing how to incorporate immunotherapies into current standard-of-care treatment protocols is essential to progress in the treatment of gynecologic malignancies.

 Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2015 Nov 24. [Epub ahead of print]

 Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56-61.

 Bourla AB, Zamarin D. Immunotherapy: new strategies for the treatment of gynecologic malignancies. Oncology (Williston Park). 2015;30:59-66, 69.

 Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33:4015-22.

 Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51-72.

 Patch AM, Christie EL, Etemadmoghadam D, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521:489-94.

 Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69-74.

 Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-99.

 The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609-15.

 Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25:32-40.

 Wu CY, Yang LH, Yang HY, et al. Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors. Clin Cancer Res. 2014;20:644-57.

 Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014-22.

 Huang J, Wang L, Cong Z, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a BRCA1 (-/-) murine model of ovarian cancer. Biochem Biophys Res Commun. 2015;463:551-6.

 Luoto KR, Kumareswaran R, Bristow RG. Tumor hypoxia as a driving force in genetic instability. Genome Integr. 2013;4:5.

 Lu Y, Chu A, Turker MS, Glazer PM. Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol Cell Biol. 2011;31:3339-50.

 Bindra RS, Gibson SL, Meng A, et al. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 2005;65:11597-604.

 Sondak VK, Smalley KS, Kudchadkar R, et al. Ipilimumab. Nat Rev Drug Discov. 2011;10:411-2.

 Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253-68.

 Huang Y, Goel S, Duda DG, et al. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73:2943-8.

 Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73:539-49.

 Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665-74.

 Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781-90.

 Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302-8.

 Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734-43.

 Ledermann JA, Perren JG, Raja FA, et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. 38th Congress of the European Society for Medical Oncology. Amsterdam, Netherlands; 27 Sep–01 Oct 2013. Abstr LBA10.

 Symonds RP, Gourley C, Davidson S, et al. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16:1515-24.

 Meng X, Huang Z, Teng F, et al. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev. 2015;41:868-76.

 Homicsko K, Coukos G. Targeting programmed cell death 1 in ovarian cancer. J Clin Oncol. 2015;33:3987-9.

 Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43-51.

 Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1:1319-23.

The advent of immunotherapy presents us with new treatment approaches in gynecologic cancers, with preliminarily promising outcomes. Multiple clinical trials are currently being conducted to better define the role of immunotherapy. Further investigation is warranted to develop and identify predictive biomarkers.

Challenges and Opportunities for Immunotherapies in Gynecologic Cancers

Surgery continues to be the cornerstone of the treatment plan for patients with soft-tissue sarcomas. The exact contribution of chemotherapy, radiation therapy, and combined chemoradiation therapy in the management of soft-tissue sarcomas is not as well defined due to a lack of level 1 evidence of the benefit of these modalities, particularly chemotherapy. The genesis of this impediment stems from the rarity and pathologic heterogeneity of soft-tissue sarcomas, which has made it difficult to sufficiently power clinical trials. As such, most of the data for neoadjuvant chemoradiation therapy stem from studies that group together multiple different histologies that can exhibit very different clinical behaviors and responses to systemic therapy. Attempts at assessing the histology-specific impact of systemic therapy have been retrospective in nature, employing historical controls or contemporary cohorts.

In this issue of ONCOLOGY, Fairweather et al review several important studies and the rationale for the use of neoadjuvant chemotherapy, radiation therapy, and chemoradiation therapy in the treatment of soft-tissue sarcomas.[1] Neoadjuvant therapy is thought to be important because it can downstage tumors; offers earlier treatment of micrometastatic disease; and can serve as an in vivo test of chemotherapy and/or radiation therapy, allowing early treatment modifications such as stopping or changing chemotherapy and decreasing the dose or field of radiation. But these benefits must be weighed with the risks of delaying surgery and the wound-healing complications that can occur from neoadjuvant therapy. The authors have highlighted several studies that, while not level 1 clinical evidence, demonstrate a benefit from neoadjuvant therapy for soft-tissue sarcomas. In these instances where there are ample observational data, we feel that staunchly supporting the dogma of the randomized controlled trial may not be beneficial to patients. These observational studies are still important in forming treatment decisions, since the rarity of some types of sarcomas will preclude high-powered studies from ever being done.[2]

The first randomized trial to show a survival benefit of adjuvant chemotherapy for osteosarcoma was completed in an era where a standard of care was lacking, despite studies from large-volume sarcoma institutions such as Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson Cancer Center, and the Mayo Clinic, which supported the use of chemotherapy as an adjunct to surgery for osteosarcoma.[3] Further, it was the addition of neoadjuvant and adjuvant chemotherapy that radically improved the outcome of patients with both bony and soft-tissue Ewing sarcoma and increased survival rates from approximately 15% with definitive surgery and radiation (or amputation) to nearly 70% today.[4] These cases illustrated that the availability of effective systemic therapy can change the course of chemoresponsive sarcomas with high metastatic potential.

Looking closer, we see that outcomes of individual chemoresponsive histologies can be improved with systemic therapy. Eilber et al demonstrated that patients with synovial sarcoma who were treated with an ifosfamide-based regimen had improved distal relapse–free survival-from 46% to 74% at 4 years compared with patients who were treated with localized therapy alone.[5] At the University of California, Los Angeles and MSKCC, 245 patients with high-risk liposarcoma of the extremities were treated with neoadjuvant or adjuvant chemotherapy and, on multivariate analysis, treatment with ifosfamide was independently associated with improved disease-specific survival compared with no chemotherapy (hazard ratio, 0.3; 

 = .01).[6] On the other hand, regardless of histology, attempts have been made to select patients who will achieve the greatest benefit from neoadjuvant/adjuvant therapy by looking at the pathologic response to neoadjuvant therapy. However, the results from these studies have been variable,[7-9] with no clear consensus on how to grade pathologic response in soft-tissue sarcomas. Some researchers have started to investigate the use of tumor standard uptake value changes with fluorodeoxyglucose positron emission tomography imaging as a possible prognostic biomarker for response to therapy/improved outcomes.[10,11]

As with other malignancies, neoadjuvant treatment has impacted sarcoma therapy by fostering a movement away from morbid amputations and toward functional limb-sparing approaches.[12] Neoadjuvant therapy has also changed the standard of care in osteosarcoma and Ewing sarcoma, demonstrating a role for its use in sarcoma subtypes for which sufficiently powered randomized clinical trials may never be done.

Fairweather et al highlight the important topic of neoadjuvant therapy for the management of soft-tissue sarcoma and the lack of level 1 clinical data in this area. They also highlight several informative observational studies that clinicians can use to counsel patients with large, high-grade sarcomas who have a ≥ 50% likelihood of developing systemic disease.[13] As such, it is critical for these patients to be evaluated and treated by an experienced multidisciplinary sarcoma program. Improvements in neoadjuvant therapy for soft-tissue sarcomas will require the development of more efficacious systemic therapies and, if possible, the performance of histology-specific, prospective, randomized clinical trials to advance the field.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. 

 Fairweather M, Keung E, Raut CP. Neoadjuvant therapy for soft-tissue sarcomas. Oncology (Williston Park). 2016;30:99-106.

Improvements in neoadjuvant therapy for soft-tissue sarcomas will require the development of more efficacious systemic therapies and, if possible, the performance of histology-specific, prospective, randomized clinical trials to advance the field.

Oncology Vol 30 No 1