Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) were initially developed with the rationale that they would inhibit the growth of tumors with EGFR overexpression.[1] Although the early clinical trials of these agents referred to “targeted” therapy, they included all patients with a diagnosis of non–small-cell lung cancer (NSCLC) progressing on front-line chemotherapy, without patient selection based on a proposed mechanism of action for the therapy under investigation. This all-inclusive strategy resulted in the induction of tumor responses in only 8.9% of lung cancer patients.[2] To find tumors that would more predictably respond to an EGFR TKI–directed treatment strategy, efforts were initiated to find appropriate biomarkers for responsiveness to EGFR TKI therapy; the first candidates were EGFR protein expression and 

amplification by fluorescence in situ hybridization.[3] However, 

 TKI–sensitizing mutations were revealed only when investigators performed an analysis of tumors that were unusual responders to EGFR TKI therapy.[4] This led to the development of clinical trials targeting the subset of patients with EGFR TKI–sensitizing mutations,[5] the results of which confirmed superior response rates and improved progression-free survival (PFS) when TKIs were used in front-line treatment as compared with chemotherapy.

Soon after EGFR TKIs had begun to be used for treatment of tumors with

 TKI–sensitizing mutations, an emergence of acquired resistance was observed,[6] with a secondary mutation in exon 20 leading to substitution of methionine for threonine at position 790 (T790M); this point mutation interfered with the ability of first and second generations of EGFR TKIs to bind to the adenosine triphosphate pocket of the tyrosine kinase domain of EGFR. An effort to overcome this resistance led to the development of a third generation of EGFR TKIs, one of which (osimertinib) is currently commercially available.[7]

However, as Dr. Levy and colleagues describe in this issue of ONCOLOGY,[8] almost half of cases of resistance to EGFR TKIs result from adaptation of cancer cells other than those with T790M mutations to EGFR TKI pressure (see Figure 2 in the current review by Levy et al: Acquired Mutations of 

 in NSCLC). Patients with primary and secondary resistance to EGFR TKIs whose tumors carry 

 mutations other than T790M should be offered participation in clinical trials such as the NCI-MATCH study (ClinicalTrials.gov identifier: NCT02465060), which assigns patients to an inhibitor therapy targeting a specific genomic aberration; for example, patients whose tumors carry acquired

 mutation receive therapy with dabrafenib (a BRAF inhibitor), whereas patients whose tumors have 

 mutation receive therapy with taselisib (an investigational phosphoinositide 3-kinase inhibitor).

Characterization of molecular mechanisms of resistance

Levy et al[8] bring up a critical point regarding the need for rebiopsy in order to understand a tumor’s mechanism of escape from EGFR TKI suppression. Citing a study by Chouaid et al,[9] they point out that rebiopsy in clinical practice is not frequently done for a number of reasons. The introduction of analysis of circulating cell-free DNA (cfDNA) originating from tumor, or “liquid biopsy,” can circumvent tumor rebiopsy challenges. There are several commercial tests available to perform genetic analysis of cfDNA, and on June 1, 2016, the first such test to specifically detect 

 mutations in plasma was approved by the US Food and Drug Administration (the cobas® EGFR Mutation Test v2). I agree with the proposal by Dr. Levy and coauthors to utilize these plasma tests early in the management algorithm of EGFR TKI–resistant lung cancer (see the authors’ Figure 3, Proposed Algorithm for EGFR TKI–Resistant Lung Cancer).

Timing of the switch to second-line therapy

In their review, Dr. Levy and colleagues describe three different strategies for treatment, which are dependent on whether progression occurs only in a few sites or in multiple new metastatic sites, and on whether disease progression is asymptomatic. These recommendations evolved at the time when no effective therapeutic options were available. I agree with the authors’ described management of oligometastatic disease with local therapies that provide additional months of disease control beyond progression following first-line EGFR TKI therapy, for example, as investigated by Yu et al[10]; however, an exact determination of which individuals with oligometastatic disease would have the greatest benefit from aggressive local therapy is lacking. Perhaps analysis of microRNA expression patterns predictive of oligoprogression would be useful in this situation.[11]

The therapeutic field is rapidly evolving, and introduction of effective therapy for tumors harboring the T790M mutation now challenges the approach of continuing first-line TKI therapy in asymptomatic patients. Therefore, I propose a modified algorithm, derived from the one included in the current review by Levy and colleagues (Figure).

Spectacular lung cancer responses to checkpoint inhibitor therapy raise questions about the place of this therapy in the management of lung cancer tumors with 

 mutation. There is the suggestion from preclinical models that EGFR pathway activation inhibits antitumor immunity by upregulation of programmed death 1 (PD-1)/programmed death ligand 1 signaling.[12] In addition, although Chen et al demonstrated that EGFR TKI therapy may enhance antitumor immunity, they found no synergistic effect in patients who received combination treatment with EGFR TKIs and an anti–PD-1 antibody.[13] In spite of these preclinical observations, two clinical trials combining therapies that target EGFR and PD-1 are underway, exploring the hypothesis that combination therapy can delay disease progression on EGFR treatment or induce responses after the emergence of primary resistance. One study, investigating combination therapy with a checkpoint inhibitor plus erlotinib or crizotinib for patients with 

-mutated stage IV NSCLC (ClinicalTrials.gov identifier: NCT01998126), has completed accrual and is following patients. The other, a study of pembrolizumab and afatinib in patients with NSCLC that is resistant to erlotinib (ClinicalTrials.gov identifier: NCT02364609), is still accruing patients. In a recent analysis of 20 clinical trials evaluating the activity of checkpoint inhibitors in the second-line setting, it was noted that benefit from this immune therapy was low in patients with 

-mutated tumors.[14] Larger datasets focusing on lung cancer with 

 mutation will be needed to define the role of checkpoint inhibitors in this EGFR TKI–resistant disease.[14]

Cancer cells undergo accelerated evolutionary changes[15]; thus, under the pressure of novel generations of EGFR TKIs, we should expect to see new mechanisms of resistance. As Dr. Levy and coauthors mention, mutation in C797S in response to treatment with osimertinib has already been observed.[16] The presence of constant adaptation of the tumor genome to new therapeutic pressures emphasizes a need for continuous monitoring of these changes, so that new treatment strategies can be designed before symptomatic disease progression occurs. “Liquid biopsies” can become useful diagnostic tools in this endeavor. Therapeutic options for the treatment of lung cancer are increasing every year and rapidly outgrow current guidelines. These advances generate the need for up-to-date reviews such as the current one by Dr. Levy et al, so that practicing oncologists can quickly adjust to new management paradigms in their practice and offer cutting-edge treatment to their patients with lung cancer.

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

 Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol. 2002;20:2240-50.

 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-32.

 Dziadziuszko R, Holm B, Skov BG, et al. Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy. Ann Oncol. 2007;18:447-52.

 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-39.

 Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-8.

 Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.

 Greig SL. Osimertinib: first global approval. Drugs. 2016;76:263-73.

 Levy BP, Rao P, Becker DJ, Becker K. Attacking a moving target: understanding resistance and managing progression in EGFR-positive lung cancer patients treated with tyrosine kinase inhibitors. Oncology (Williston Park). 2016;30:601-12.

 Chouaid C, Dujon C, Do P, et al. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01). Lung Cancer. 2014;86:170-3.

 Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8:346-51.

 Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One. 2012;7:e50141.

 Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355-63.

 Chen N, Fang W, Zhan J, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol. 2015;10:910-23.

 Melosky B, Chu Q, Juergens R, et al. Pointed progress in second-line advanced non-small-cell lung cancer: the rapidly evolving field of checkpoint inhibition. J Clin Oncol. 2016;34:1676-88.

 Willyard C. Cancer therapy: an evolved approach. Nature. 2016;532:166-8.

 Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21:560-2.

Articles

Cancer cells undergo accelerated evolutionary changes; thus, under the pressure of novel generations of EGFR TKIs, we should expect to see new mechanisms of resistance.

Management of Resistance to EGFR TKI–Targeted Therapy of Lung Cancer: Lessons in Monitoring Cancer Evolution

The diagnosis and treatment of depression in the cancer setting can improve patients’ quality of life, their adherence to therapy recommendations, and the illness experience, all of which may affect survival outcomes.[1,2] In the past, the attitude toward the management of depression in patients with cancer originated from the idea that all cancer patients suffered from depression of some form, for which little could be done. There are now many effective treatments for depression in cancer patients; an oncologist can diagnose depression and initiate its treatment as a means to alleviate substantial suffering, contribute to better health outcomes, and provide comprehensive patient-centered care.

A 47-year-old mother of two is diagnosed with locally advanced, estrogen and progesterone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and undergoes breast-conserving lumpectomy. She is a candidate for adjuvant chemotherapy because of her positive nodal status. At diagnosis she reports coping well and scores under 4 on the Distress Thermometer and Problem List (DT&PL).[3] During a routine chemotherapy infusion, a nurse-administered distress screen reveals a DT&PL score of 9 (range, 0–10), and the patient reports an increased feeling of “going through the motions” as if in a trance-like state, episodes of sudden tearfulness, and feeling like she is “out of control.” Concerned for her patient, the oncologist remembers a helpful mnemonic device from medical school for the diagnosis of depression-S-I-G-E-C-A-P-S (Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicidal; Table 1)-and asks two additional screening questions from the Patient Health Questionnaire-2 (PHQ-2)[4]: 1) During the past 2 weeks, have you often been bothered by feeling down, depressed, or hopeless? and 2) During the past 2 weeks, have you often been bothered by little interest or pleasure in doing things? The oncologist knows that even simply asking, “Are you depressed?” can be used as a screening tool.[5]

To determine the patient’s functional status with newly diagnosed cancer, the oncologist asks if the patient has been struggling with her responsibilities or finding it difficult to complete necessary tasks. The patient reports feeling depressed but still looks forward to her children’s school events (“future-oriented thinking”) and reports that she enjoys her friends’ company (ie, she is not anhedonic). She has a good support system and help from her husband. During the interview, the patient reports feeling safe, denies any self-harm or self-injurious thoughts, denies use of illicit substances and alcohol, and denies having any access to firearms. The oncologist discusses an initial treatment plan with her that includes individual counseling and meeting other women with breast cancer in a support group. Medications are discussed as additional options to treat her symptoms and to optimize her health.

Distress screening should be implemented at the time of diagnosis, at recurrence of disease, and routinely every 6 months, or whenever clinically indicated.[6] This approach is an important first step in providing basic psychosocial care in oncology. Although many oncology practices report that they address psychosocial needs (most frequently by asking their patients if they are depressed),[7] depression is often underdiagnosed or mistaken for another disorder (Table 2).[8,9] Screening for depression and understanding depressive symptoms provide opportunities for the oncologist to build empathic trust with the patient.[10] The next step after distress screening is a comprehensive clinical interview to further evaluate the nature of the depressive symptoms. Diagnostic tests should be ordered to rule out other depression mimickers (Table 3), and the assessment should focus on the patient’s symptom burden (eg, does he/she meet Diagnostic and Statistical Manual of Mental Disorders [DSMV] criteria for depression? [Table 1]), functional status (eg, are his/her relationships, self-care, or roles impaired?), and the presence of any dangerous behaviors (eg, excessive drug/alcohol use, medication abuse, access to firearms, physical or sexual abuse). Additionally, there are several anticancer medications that have been associated with depressive signs and symptoms, and it is important for oncologists to know about these drugs (Table 4).

In two-thirds of cancer patients who experience depression, the distress may be related to cancer treatments or symptoms, may be situational, or may be addressed with problem-solving.[11] However, the combination of symptoms and functional impairment typically warrants psychiatric treatment with therapy and/or medications. The vignette depicts situational depressive symptoms with minimal functional impairment and good prognostic risk factors (ie, support system). Options for effective treatment for cancer patients with depression include individual counseling, group support, cognitive behavioral or interpersonal therapy, and/or pastoral counseling.[12,13] Medications should be recommended for more severe symptoms.[14] The oncologist can emphasize the benefits of psychiatric care as a means to better health. Reframing negative cognitions (ie, correcting erroneous thoughts) and supporting the “ego” function (eg, focusing on what they are doing well) are effective interventions that provide emotional support. Patients highly value their relationships with their oncologic providers, and positive support and encouragement are also meaningful
interventions.

The patient’s coping ability improves with the aforementioned interventions. She completes her adjuvant therapies and does well on her antihormonal therapy. However, she has a recurrence of disease after 8 years. At this time, she becomes despondent and is struggling to complete daily activities. She reports sleeping poorly and lack of appetite, and no longer enjoys spending time with her friends and family or pursuing her interests. She has preoccupations with death and has difficulty concentrating, but denies any suicidal ideation or death wishes. Reluctantly, she agrees to engage in individual therapy but does not want to discuss medication. Given her symptom burden and inability to satisfactorily complete tasks, the oncologist encourages her to consider a sleep aid and an antidepressant to treat her major depressive symptoms (ie, she has 5 of 9 S-I-G-E-C-A-P-S symptoms for over 2 weeks, and functional impairment; Table 1).

Drawing upon a positive, trusting therapeutic alliance in the oncologist-patient relationship may be enormously helpful for patients. Mild to moderate distress or depressive symptoms, without significant functional impairment, may be addressed with short-term supportive, cognitive behavioral, or behavioral activation therapies. Many supportive-type therapies may be used, such as expressive-supportive group therapy, individual cognitive behavioral therapy, pastoral counseling or religious services, and/or meditative/mindfulness practices. Therapeutic approaches should be drawn from existing guidelines from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO), in addition to patients’ preferences, to promote adherence.[6,15] The oncology team should commit to helping patients engage in appropriate therapies.[16]

As the “gatekeeper” to mental health services, it is also important for the oncology team to be aware of potential red flags in either safety or functional impairment, which occur in more severe depressive states (ie, those meeting DSMV criteria for a major depressive episode). Greater symptom burden with functional impairment was witnessed in the patient in the second part of the vignette. Although previous therapies should again be suggested, medications to start treating her depressive symptoms should also be encouraged. Antidepressant medications are typically chosen based on the following factors: 1) a patient’s previous experience with antidepressant medication (did it work and was it titrated appropriately?); 2) utilization of medication side effect profile (eg, sedating vs energizing, or causing somnolence, appetite stimulation, sexual side effects); 3) other depression or cancer-related side effects; 4) cost; and 5) adherence (Table 5).

Greater attention is being devoted to quality-of-life issues for patients with cancer, and adequate treatment of depression is crucial given high prevalence rates.[17] Depression treatment in the oncology clinic setting is a component of early or primary palliative care that is associated with improved patient outcomes.[18-20] Although there are challenges to accessing psycho-oncologic care, the collaborative and integrated care models are approaches for early diagnosis and treatment, wherein a psychiatric consultant serves as a liaison to oncologists.[21] Additionally, psychosocial care should be provided according to patients’ preferences (eg, patient-reported outcome measures) as much as possible.[17]

Specialized psychosocial care for cancer patients is not always accessible, highlighting the need for basic psychiatric care in the oncology clinic, as well as the need for collaboration with psycho-oncology consultants.[22,23] Leveraging the trust that patients place in their oncology care teams in order to recognize and begin treatments for depression is key to providing adequate depressive symptom relief on a large scale. Simply discussing the possibility of depression can itself be therapeutic for patients, reduce mental health stigma, and preclude depressive behaviors, such as isolation. The SMaRT Oncology-1, -2, and -3 collaborative trials provide an effective framework for primary depression care by oncology teams collaborating with mental health professionals.[24-26]

This vignette emphasizes the provision of initial treatment approaches according to ASCO and NCCN guidelines in the care of patients with depression within the oncology setting. It illustrates a step-wise approach to the care of patients with depression, based on symptom severity, functional impairment, and safety assessment. The differential diagnosis, along with medical and psychological evaluations of depression, is discussed. Distress and depression screening, and the diagnostic interview, are frequently considered therapeutic by patients. The prescribing of psychotropic medications should be approached as a dedicated therapeutic intervention, with attention to tolerability, drug-drug interactions, and signs of effectiveness from the patient and people who are close to the patient. Future research should continue to focus on integrated psycho-oncologic care to improve outcomes for patients and healthcare systems.

 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. 

 Pinquart M, Duberstein PR. Depression and cancer mortality: a meta-analysis. Psychol Med. 2010;40:1797-810.

 Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer. 2009;115:5349-61.

 Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.

 Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41:1284-92.

 Chochinov HM, Wilson KG, Enns M, Lander S. “Are you depressed?” Screening for depression in the terminally ill. Am J Psychiatry. 1997;154:674-6.

 Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol. 2014;32:1605-19.

 Muriel AC, Hwang VS, Kornblith A, et al. Management of psychosocial distress by oncologists. Psychiatr Serv. 2009;60:1132-4.

 Fallowfield L, Ratcliffe D, Jenkins V, Saul J. Psychiatric morbidity and its recognition by doctors in patients with cancer. Br J Cancer. 2001;84:1011-5.

 Walker J, Hansen CH, Martin P, et al. Prevalence, associations, and adequacy of treatment of major depression in patients with cancer: a cross-sectional analysis of routinely collected clinical data. Lancet Psychiatry. 2014;1:343-50.

 Pollak KI, Arnold RM, Jeffreys AS, et al. Oncologist communication about emotion during visits with patients with advanced cancer. J Clin Oncol. 2007;25:5748-52.

 Vodermaier A, Linden W, Siu C. Screening for emotional distress in cancer patients: a systematic review of assessment instruments. J Natl Cancer Inst. 2009;101:1464-88.

 Newell SA, Sanson-Fisher RW, Savolainen NJ. Systematic review of psychological therapies for cancer patients: overview and recommendations for future research. J Natl Cancer Inst. 2002;94:558-84.

 Antoni MH. Psychosocial intervention effects on adaptation, disease course and biobehavioral processes in cancer. Brain Behav Immun. 2013;30(suppl):S88-S98.

 Li M, Fitzgerald P, Rodin G. Evidence-based treatment of depression in patients with cancer. J Clin Oncol. 2012;30:1187-96.

 Holland JC, Bultz BD; National Comprehensive Cancer Network. The NCCN guideline for distress management: a case for making distress the sixth vital sign. J Natl Compr Canc Netw. 2007;5:3-7.

 Wein S, Sulkes A, Stemmer S. The oncologist’s role in managing depression, anxiety, and demoralization with advanced cancer. Cancer J. 2010;16:493-9.

 Fallowfield L, Jenkins V. Psychosocial/survivorship issues in breast cancer: are we doing better? J Natl Cancer Inst. 2015;107:335.

 Gaertner J, Weingartner V, Wolf J, Voltz R. Early palliative care for patients with advanced cancer: how to make it work? Curr Opin Oncol. 2013;25:342-52.

 Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-42.

 Bakitas MA, Tosteson TD, Li Z, et al. Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial. J Clin Oncol. 2015;33:1438-45.

 Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30:880-7.

 Malowney M, Keltz S, Fischer D, Boyd JW. Availability of outpatient care from psychiatrists: a simulated-patient study in three U.S. cities. Psychiatr Serv. 2015;66:94-6.

 McFarland DC, Johnson Shen M, Harris K, et al. ReCAP: Would women with breast cancer prefer to receive an antidepressant for anxiety or depression from their oncologist? J Oncol Pract. 2016;12:172-4.

 Sharpe M, Walker J, Holm Hansen C, et al. Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): a multicentre randomised controlled effectiveness trial. Lancet. 2014;384:1099-108.

 Walker J, Hansen CH, Martin P, et al. Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer. Lancet Oncol. 2014;15:1168-76.

 Strong V, Waters R, Hibberd C, et al. Management of depression for people with cancer (SMaRT oncology 1): a randomised trial. Lancet. 2008;372:40-8.

 Cowles MK, Nemeroff C. Depression as a systemic illness. In: Blumenfield M, Strain JJ, editors. Psychosomatic medicine. Philadelphia: Lippincott Williams & Williams; 2006. p. 50.

The diagnosis and treatment of depression in the cancer setting can improve patients’ quality of life, their adherence to therapy recommendations, and the illness experience, all of which may affect survival outcomes.

Managing Depression in Patients With Cancer

Despite a decrease in incidence, gastric cancer continues to be the third leading cause of cancer-related death worldwide.[1] For localized disease, surgery offers the best chance for cure. Despite surgery with curative intent, however, many patients experience recurrences, leading to dismal outcomes. With the goal of improving survival, neoadjuvant and adjuvant therapies have emerged. However, there are significant differences between countries and regions with regard to the management of localized gastric cancer. Dr. Chan and colleagues have provided an instructive article outlining current strategies used in the treatment of localized gastric cancer.[2] We should emphasize that for appropriate staging, a complete evaluation with computed tomography imaging, endoscopy with endoscopic ultrasound, and staging laparoscopy is recommended in all patients with localized disease.[3,4]

In Asia, adjuvant chemotherapy is the recommended treatment following a D2 gastrectomy,[5,6] while in Europe and Canada, perioperative chemotherapy is preferred for resectable disease.[7] Alternatively, in the United States, adjuvant chemoradiation has been popular, based on results from the Intergroup 0116 trial[8]; however, the addition of chemoradiation in this study seems to have compensated for the suboptimal surgery performed prior to study enrollment, raising questions about the role of chemoradiation after extensive lymph node dissection. Nevertheless, important limitations exist with regard to the application of results from one region to another: differences in population, in surgical approach, and in the biology of the disease have been recognized as barriers to the establishment of a consensus regarding the optimal treatment plan. One aspect of care that should be settled quickly is the adoption of D2 gastrectomy as the standard surgery for localized gastric cancer. While results from Western trials support alternate surgical approaches, D2 dissection increases the R0 resection rate and may improve survival in some selected node-positive patients.[9] The extent of lymphadenectomy contributes to the improved survival rates seen in Asian patients compared with Western patients.[5-8]

But what is the best approach to adjunctive treatment? Adjuvant or neoadjuvant? A multidisciplinary approach with an experienced team should be the starting point when we treat patients with gastric cancer. Adjuvant chemotherapy is an acceptable treatment in Western patients who have undergone extensive nodal dissection, while chemoradiation should be reserved for patients who have had less than a D1 dissection (even though, by today’s standards, patients should not undergo less than a D1 dissection). The additional survival benefit of adjuvant chemoradiation in the setting of a D2 dissection has not been established; however, the Adjuvant Chemoradiation Therapy in Stomach Tumors (ARTIST) trial suggested that patients with node-positive disease might benefit from additional adjuvant chemoradiation.[10] The ARTIST-II trial will help clarify the benefit of this approach in node-positive disease (ClinicalTrials.gov identifier: NCT01761461). Recent results from the Chemoradiotherapy After Induction Chemotherapy in Cancer of the Stomach (CRITICS) trial showed no significant difference in overall survival between postoperative chemotherapy and chemoradiotherapy.[11] These results suggest that patient survival is similar regardless of postoperative chemotherapy or radiotherapy if adequate surgery was performed.

The difficulty of delivering treatment in the adjuvant setting on account of postsurgical recovery makes the neoadjuvant approach reasonable, as therapy in this setting is more easily tolerated. Neoadjuvant strategies include preoperative chemotherapy and chemoradiation therapy. Neoadjuvant treatment has the advantage of tumor downstaging, resulting in improved surgical margins and reduced micrometastatic disease. Perioperative chemotherapy has been the standard practice in Western countries, based on the results of the MAGIC trial, yet only 40% of patients in this trial were able to complete the postoperative chemotherapy of the trial protocol due to increased toxicity and poor tolerance.[7] Should we therefore consider making preoperative therapy standard? A three-step approach involving preoperative chemotherapy and chemoradiation has demonstrated a high R0 resection rate and pathologic complete response rate, which could translate to an improved survival benefit.[12-14] Additionally, locoregional recurrence rates are significantly decreased in patients who receive preoperative radiation. This suggests that preoperative therapy is feasible and may provide a survival benefit in patients with gastric cancer. Currently, the Australian Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma (TOPGEAR) trial (ClinicalTrials.gov identifier: NCT01924819) is evaluating preoperative chemoradiation, and the next phase II study (CRITICS II) will evaluate preoperative strategies, including chemoradiation; the results of these trials might change our current standard of care in the West.

Biologic-driven strategies have also been the subject of research, although the results have been rather disappointing in localized gastric cancer. Targeting the human epidermal growth factor receptor 2 (HER2) pathway with trastuzumab had positive results in the metastatic setting, and this approach might offer some promise in the neoadjuvant setting; however, phase III trials are needed to evaluate the targeting of HER2-amplified gastric cancer in this setting.

Current methods of treatment still have a small impact on the survival of patients with localized disease. Improved understanding of the underlying mutations seen in gastric cancer might suggest alternative treatments and ways to better select patients. The targeting of appropriate pathways and the introduction of immunotherapy have marked a new era in the treatment of solid tumors. The positive results seen with immunotherapy in other malignancies have led researchers to investigate immunotherapy in gastric cancer treatment. Trials of checkpoint inhibitors, alone or in combination with other immunomodulating agents, for the treatment of metastatic gastric cancer are currently ongoing (ClinicalTrials.gov identifier: NCT01928394). Preliminary results are promising[15] and provide a proof of concept that the addition of these checkpoint inhibitors in either the neoadjuvant or adjuvant setting may be able to reshape the future of the treatment of localized gastric cancer.

 Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-E386.

 Chan BA, Jang RW, Wong RKS, et al. Improving outcomes in resectable gastric cancer: a review of current and future strategies. Oncology (Williston Park). 2016;30:635-45.

 Abdalla EK, Pisters PW. Staging and preoperative evaluation of upper gastrointestinal malignancies. Semin Oncol. 2004;31:513-29.

 Kwee RM, Kwee TC. Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol. 2007;25:2107-16.

 Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011;29:4387-93.

 Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:1389-96.

 Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11-20.

 Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725-30.

 Roukos DH. Current advances and changes in treatment strategy may improve survival and quality of life in patients with potentially curable gastric cancer. Ann Surg Oncol. 1999;6:46-56.

 Lee J, Lim do H, Kim S, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012;30:268-73.

 Verheij M, Janset EPM, Cats A, et al. A multicenter randomized phase III trial of neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy in resectable gastric cancer: first results from the CRITICS study. J Clin Oncol. 2016;34(suppl):abstr 4000.

 Ajani JA, Mansfield PF, Crane CH, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol. 2005;23:1237-44.

 Ajani JA, Mansfield PF, Janjan N, et al. Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol. 2004;22:2774-80.

 Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24:3953-8.

 Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: phase I/II, open-label study of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol. 2016;34(suppl):abstr 4010.

Current methods of treatment still have a small impact on the survival of patients with localized disease. Improved understanding of the underlying mutations seen in gastric cancer might suggest alternative treatments and ways to better select patients.

Oncology Vol 30 No 7

Management of Resistance to EGFR TKI–Targeted Therapy of Lung Cancer: Lessons in Monitoring Cancer Evolution

Managing Depression in Patients With Cancer

Adjunctive Therapy of Gastric Cancer: Moving the Field Forward