The journal ONCOLOGY® provides oncology professionals with practical and timely clinical information necessary to deliver the highest level of patient care. Expert authors and peer review ensure the quality of the journal’s articles and features. Focused discussions capture key clinical take-aways for application in today’s time-constrained practice environment.

Historically, radiation therapy has played a limited role in the management of renal cell carcinoma because early studies showed that it had no benefit in the neoadjuvant or adjuvant settings. Thus, radiation has typically been employed for only palliation of metastatic sites. As the ability to deliver conformal high-dose-per-fraction radiation became available, studies began to show excellent local control when treating oligometastatic sites of renal cell carcinoma with stereotactic body radiation therapy (SBRT). Recently, SBRT has been studied in the management of the primary tumor in nonsurgical patients with localized renal cell carcinoma. Excellent local control rates and low rates of treatment-related toxicity were reported with single-fraction (26 Gy) and multi-fraction (36 to 45 Gy in 3 fractions or 40 to 50 Gy in 5 fractions) regimens. While the evidence to date is limited by small cohort sizes and variability in treatment approaches, the reported outcomes are promising. Ongoing studies will continue to define how renal SBRT fits into the management of patients who are not eligible for surgery.

Curative-intent treatment of localized renal cell carcinoma entails surgical resection with a radical or partial nephrectomy. Early randomized studies failed to show a survival benefit with the addition of neoadjuvant[1,2] or adjuvant[3,4] radiotherapy. Moreover, renal cell carcinoma is considered a radioresistant histology based on in vitro studies.[5] Thus, radiation therapy has historically been limited to the palliative setting for patients with renal cell carcinoma. Stereotactic radiosurgery (SRS) has long been used for effective local control of intracranial metastases from renal cell carcinoma, most often with a single fraction of high-dose radiation therapy.[6-9] With the advent of technology allowing for safe delivery of highly conformal high-dose-per-fraction radiation therapy to extracranial sites, stereotactic body radiation therapy (SBRT) is now widely used to treat oligometastatic disease. Excellent local control rates of higher than 90% at 1 year have been demonstrated for metastatic renal cell carcinoma lesions in the spine[8,10-12] and visceral sites.[9,13-15] The findings of these clinical studies coincided with another study demonstrating the efficacy of ablative high-dose-per-fraction radiation therapy in treating renal cell carcinoma in a mouse model.[16] These results suggest that ablative doses of radiation therapy delivered with stereotactic techniques have the potential to impact outcomes in renal cell carcinoma, whereas the role of standard fractionated radiation therapy is limited.

In light of the promising outcomes seen with SBRT for metastatic sites of renal cell carcinoma, renal SBRT is increasingly being evaluated for treatment of the primary tumor in nonsurgical candidates. There are several retrospective[17-20] and prospective[13,21-28] studies evaluating the role of SBRT in the treatment of non-metastatic renal cell carcinoma, which have demonstrated excellent local control rates with minimal toxicity, and additional studies are ongoing. This review summarizes the current evidence supporting the use of SBRT as treatment for inoperable renal cell carcinoma, with a focus on prospective studies. We will provide recommendations for patient selection and review the technical aspects of treatment, as well as the expected toxicities.

Review of the Evidence for SBRT in Localized Renal Cell Carcinoma

Although only a limited number of prospective studies evaluating SBRT in localized renal cell carcinoma have been published, the results are encouraging (

). Interpretation of these studies is limited by the small number of patients treated, lack of long-term follow-up, and the varying dose fractionation schemes. The trials evaluated cohorts of 10 to 40 medically inoperable patients treated with doses of 25 to 26 Gy in 1 fraction, 24 to 48 Gy in 4 fractions, or 21 to 48 Gy in 3 fractions. With an average follow-up of 13 to 52 months, local control rates ranged from 87% to 100%. In the most recently published prospective series, 33 patients with renal cell carcinoma received SBRT to the primary tumor (26 Gy in 1 fraction or 42 Gy in 3 fractions for larger tumors), and the 2-year local control rate was 100%.[28] A larger study published in 2015 included 40 patients who received 25 Gy in a single fraction to primary renal tumors (75% of which were renal cell carcinoma), and the 9-month local control rate was 98%, though longer follow-up is lacking.[21] While these prospective studies demonstrate promising rates of local control with SBRT, there are no completed randomized phase III trials to date comparing SBRT with other local therapy modalities.

The prospective dose escalation studies evaluated doses ranging from 21 to 48 Gy in 3 fractions[23,25] and 24 to 48 Gy in 4 fractions.[24] For the 3-fraction studies, local failure only occurred in 1 patient receiving 21 Gy and 1 patient receiving 27 Gy.[23,25] These results suggest that for 3-fraction regimens, a minimum of 11 Gy per fraction should be considered, which is the minimum dose at which no patient in these studies experienced a local failure. This is consistent with the consensus statement from the International Radiosurgery Oncology Consortium for Kidney, which recommends a total dose of 36 to 45 Gy for 3-fraction regimens.[29] For 5-fraction regimens, a total dose of 40 to 50 Gy is recommended. In the 4-fraction dose-escalation study, the local control rate for the 15 patients with evaluable responses was 100%.[24] The study did not report on toxicity levels for individual doses, but overall, no dose-limiting toxicity was reached (defined as any treatment-related Ã¢‰¥ grade 3 gastrointestinal/genitourinary toxicity or any grade 4 toxicity). For treatment in a single fraction, 25 to 26 Gy has been studied,[21,22,26,28] with no significant difference in toxicities or negative impact on local control rates compared with multi-fraction regimens.[24-28] Thus, multiple fractionation schemes appear to be effective. While studies are lacking to compare these regimens, total dose and fraction size should be influenced by the size of the primary tumor and its proximity to the adjacent normal tissues.

Retrospective studies of SBRT in place of surgery for renal cell carcinoma also showed excellent local control outcomes, ranging from 64.8% to 100% (

). The largest series of 40 patients with renal tumors (60% of which were renal cell carcinoma) reported a 92.7% local control rate with 21 to 48 Gy in 3 fractions, with a median follow-up of approximately 18 months.[20] In the second largest series of 16 patients treated with 30 to 40 Gy in 5 fractions, the local control rate was 100%, with a median follow-up of 19 months.[17] Only one study demonstrated a suboptimal 1-year local control rate, of 64.8%, for patients treated with 60 to 85 Gy in 5 to 7 fractions, but the study population included patients with more advanced disease who had failed in the contralateral kidney after a prior nephrectomy.[30] The efficacy of renal SBRT is further supported by a meta-analysis of both prospective and retrospective studies, which showed an estimated weighted 2-year local control rate of 92.9%.[31]

Delivery of precise, highly conformal ablative doses of radiation to the kidney requires reproducible patient setup and appropriate respiratory motion management. Technical approaches utilized in published studies are varied (

). Respiratory motion management is essential to deliver a highly conformal treatment because the mean displacement of the kidneys with respiration is 0.75 cm, with a range of 0.10 to 2.15 cm for the left kidney and 0.11 to 1.92 for the right kidney.[32] Most displacement occurs in the superior-inferior direction. Furthermore, on-treatment imaging is essential given variability in patient setup.[33] With dual-vacuum immobilization (or Vac-LokTM™ Cushions with abdominal compression), the average three-dimensional displacement of the target post-treatment was restricted to 1 mm, with a maximal displacement in any direction of ≤ 3 mm. This suggests that, with adequate immobilization, respiratory excursion and interfraction motion is limited, and respiratory gating methods may not be essential.[34] The most recent prospective series used LINAC-based SBRT without fiducials and a four-dimensional (4D) CT simulation for respiratory motion management.[22,28] Other series utilizing CyberKnife® treatment platforms employed real-time target tracking of implanted gold fiducials.[21,24] Planning tumor volume (PTV) expansions differ based on treatment platform, with real-time target tracking of gold fiducials and CyberKnife® utilizing a PTV of 0.0 to 3.0 mm,[24] and LINAC-based SBRT based on 4D CT with no fiducials or target tracking utilizing a PTV of 5.0 mm.[22,28] Tables detailing suggested dose constraint values for different dose/fractionation schemes are reported by Pham[26] and Siva.[29]

One of the challenges of SBRT is the interpretation of post-treatment radiographic studies, and defining characteristics that coincide with treatment response or recurrence. Renal cell carcinoma is generally slow-growing, and it has a similarly slow radiographic response to SBRT. The largest study of tumor response included 41 tumors treated with SBRT. The mean pretreatment linear growth rate was 0.68 cm per year; post-treatment, the linear growth rate regressed by an average of 0.37 cm per year. The study found no significant changes in enhancement on CT or MRI when comparing pre- and post-treatment imaging.[20]

In general, toxicity rates for SBRT in primary renal cell carcinoma are favorable (Tables 1 and 2). In the largest prospective series evaluating SBRT to 25 Gy in 1 fraction for renal tumors, there were no grade > 1 toxicities.[21] In the most recent prospective study, only 1 patient developed grade 3 toxicity (fatigue), with 21% experiencing grade 2 toxicity (mostly fatigue and nausea), and 58% of patients experiencing grade 1 toxicity, mostly comprised of chest wall pain and fatigue.[28]

Of concern is the potential for SBRT to impact renal function. A study of 21 patients treated with SBRT showed that the glomerular filtration rate (GFR) decreased by 8.7 mL per minute on average at 1 year post-treatment.[22] Similarly, in a pooled analysis of 223 patients treated with renal SBRT, the average GFR decreased by ~5.5 mL per minute after SBRT.[35] For more fractionated regimens, a dose distribution of 20 to 30 Gy in 10 fractions had a strong correlation with renal atrophy as assessed on CT scan.[36] In a case report of a patient treated with 26 Gy in 1 fraction, regional kidney function after SBRT was assessed with 

Tc dimercaptosuccinic acid single photon emission tomography/CT, and renal function was preserved in regions receiving less than 13 Gy in a single fraction.[37] Although most nephrotoxicity experienced with renal SBRT is subclinical, toxicity is increased in patients with underlying chronic kidney disease (CKD), with reported cases of stage 4 to 5 CKD requiring dialysis after SBRT.[17] The low toxicity rates may be due to the parallel function of nephrons, allowing for preserved renal function if a substantial portion of normal kidney is spared. Long-term toxicity after SBRT, however, is unknown.

Surgery remains the standard curative-intent therapy for localized renal cell carcinoma. Thus, SBRT for renal cell carcinoma should be considered only in patients who have contraindications to surgery. Some studies also treated renal cell carcinoma patients with SBRT if they refused surgery.[22,26,28] However, patients should be educated that surgery is the standard of care prior to considering SBRT in this population. Recent German guidelines on the role of radiation therapy in renal cell carcinoma state that SBRT is currently considered an experimental option due to the small number of patients reported in the literature, though it will likely have an increased role in the future as results from ongoing studies continue to emerge.[38]

Renal SBRT has also been studied in several other patient populations, including patients with metastatic disease as an alternative to cytoreductive nephrectomy,[39] those with bilateral renal tumors,[30,40] and those with a contralateral recurrence after nephrectomy.[41] The studies of these patient populations are small, and recommendation for SBRT in these settings should be made only after careful consideration of other options with acknowledgement of the sparsity of outcomes data.

The role of SBRT in localized renal cell carcinoma is actively being defined, and given its excellent short-term local control rates and minimal toxicity, it will likely play a more prominent role in future management. There are several ongoing studies of SBRT as an alternative to surgery in localized renal cell carcinoma, which should add to the currently limited body of evidence supporting its use. One phase II study is evaluating renal impairment in 30 inoperable renal cell carcinoma patients treated with SBRT at 27.5 to 40 Gy in 5 fractions (ClinicalTrials.gov identifier: NCT03747133). Another study plans to enroll 30 inoperable patients to evaluate quality of life after SBRT (35 to 40 Gy in 5 fractions), as well as cost effectiveness (ClinicalTrials.gov identifier: NCT03108703). The ARREST study will treat a similar cohort of 30 patients with SBRT (35 Gy in 5 fractions) and assess for toxicity as a primary endpoint (ClinicalTrials.gov identifier: NCT02853162). FASTRACK II, the largest ongoing phase II study, plans to treat 70 renal cell carcinoma patients with SBRT-either 26 Gy in 1 fraction (if < 4 cm) or 42 Gy in 3 fractions (if > 4 cm), with a primary outcome of freedom from local progression assessed by Response Evaluation Criteria in Solid Tumors (RECIST; ClinicalTrials.gov identifier: NCT02613819). Another phase II study plans to enroll 16 inoperable patients and treat them with SBRT to 36 Gy in 3 fractions, 40 Gy in 4 fractions, or 40 Gy in 5 fractions, to evaluate local control (ClinicalTrials.gov identifier: NCT02141919).

Current studies are also evaluating the efficacy of renal SBRT in combination with other local or systemic therapies. A phase I dose-escalation study is ongoing to evaluate SBRT doses of 30, 40, and 50 Gy in 5 fractions followed by microwave ablation, with a primary outcome of dose-limiting toxicity (ClinicalTrials.gov identifier: NCT02782715). An area of particular interest is the potential for a synergistic effect with SBRT and concomitant immunotherapy. Recent studies have demonstrated the effectiveness of SBRT and immunotherapy in mouse models of renal cell carcinoma,[42] specifically that SBRT has immunomodulatory effects in patients undergoing cytoreductive nephrectomy after SBRT.[43] In one mouse model of renal cell carcinoma, investigators showed that the combination of ablative radiotherapy and programmed death 1 (PD-1) blockade induced near-complete regression of the irradiated primary tumor, as compared with radiation alone or radiation plus a control antibody. There was also a significant abscopal effect, with more than 50% reduction in the size of nonirradiated secondary tumors.[42] Another group analyzed the immunomodulatory effects of SBRT in renal cell carcinoma by treating patients with metastatic disease with SBRT to the primary tumor followed by cytoreductive nephrectomy. They showed that SBRT-treated tumors had increased calreticulin and tumor-associated antigen expression. In addition, they found increased proliferating CD8+ T cells and FOXP3+ cells in the SBRT-treated tumors compared with controls that received no neoadjuvant SBRT. These studies, and others, have led to the many active clinical trials evaluating the efficacy of immunotherapy and other biologic agents in combination with SBRT, both published[41] and yet unpublished (ClinicalTrials.gov identifiers: NCT01896271, NCT02781506, NCT02306954, and NCT02334709).

The current state of the literature demonstrates the efficacy and tolerability of renal SBRT in patients with nonoperative renal cell carcinoma, though studies are early-phase and limited by small cohort sizes and lack of long-term follow-up for toxicities and outcomes. Thus, surgery remains the standard of care for localized renal cell carcinoma. However, in nonoperative candidates, SBRT can be offered in a single fraction of 26 Gy; 3 fractions to a total dose of 36 to 45 Gy; or 5 fractions to a total dose of 40 to 50 Gy. The high rates of local control reported in the prospective studies to date suggest that renal SBRT has the potential to impact outcomes for nonsurgical patients. In addition, studies evaluating SBRT in combination with immunotherapy or targeted agents may improve outcomes for patients with more advanced disease. Thus, SBRT is a reasonable treatment option in the current management of nonsurgical patients with localized renal cell carcinoma, and ongoing and future studies will better define its place in multimodality management.

• Single-institution prospective studies have shown high rates of local control and acceptable rates of toxicity when renal stereotactic body radiation therapy (SBRT) is employed in nonoperative candidates with renal cell carcinoma.

• Longer follow-up is needed to evaluate long-term outcomes and toxicities after renal SBRT.

• Renal SBRT can be considered for select patients with localized renal cell carcinoma who are not candidates for surgery.

• Further prospective studies are necessary to better define the role of SBRT in localized renal cell carcinoma.

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

Local Control Is Not the Only Outcome of Interest in RCC

The authors of the accompanying article are to be congratulated for a highly detailed and informative review of a fast-evolving concept in the care of kidney cancer patients, namely the role of radiation therapy in localized kidney cancer. The role of radiation therapy for the treatment of 

 kidney cancer metastases is well established, and most modern approaches favor higher-fraction, shorter-duration treatments, which is certainly favored by both patients and their caregivers. At our very high-volume kidney cancer center, I routinely refer all of my patients with symptomatic kidney cancer metastases for site-directed treatment utilizing either radiosurgery or percutaneous approaches. The benefit is clear.

However, with regard to localized kidney cancer, the gold-standard curative therapy is currently surgery. The field has moved to active surveillance for many patients who are not candidates for surgical treatment. The data supporting active surveillance are extensive, with long-term studies showing that active surveillance of small renal masses is associated with excellent survival. In this review, the authors correctly observe that the local control of kidney masses after radiation is excellent. Further, they provide guidance on dose, as well as important observations on technical aspects of dose delivery, including the use of fiducial markers-which are especially important given the significant displacement of the kidney with normal respiration.

However, local control, if measured purely by size, is not an appropriate measure

. After radiotherapy, is the kidney cancer dead or not? Control of growth itself is not the oncologic outcome of interest per se. It is notable that the most recent publication cited by the authors demonstrates a 100% local control rate, but the development of distant metastases in 11% of patients.[1] If radiotherapy was working to kill the tumor, this number compares unfavorably to active surveillance. For a population of patients who have essentially T1 tumors, this is higher than expected, even among patients who I would counsel regarding active surveillance. The ideal trial would randomize patients to active surveillance or radiotherapy, with both local and distant endpoints, in addition to quality-of-life endpoints.

Renal function after radiation must be considered, as the authors point out. Radiation to the kidneys produces modest declines in kidney function, which is very important information. But, clinically, many patients experience declines in kidney function over time, particularly those with highly compromised kidney function. Patients who have stage 4 or 5 chronic kidney disease may not be able to tolerate the small declines in kidney function associated with radiation therapy.

As it currently stands, radiation therapy for localized kidney cancer should be considered only in the context of clinical trials, particularly prospective trials. In my humble opinion, the ideal study would be prospective in nature, evaluating patients with biopsy-proven, high-grade kidney cancer that is 

, meaning it meets the criteria for treatment. As the field learns more from genetic studies, such as the TRACERx Renal trial,[2] we will be able to distinguish lethal tumors from indolent tumors. Many times, the indolent tumors are found in older, frail patients with comorbidities.

Possibly the most exciting prospect of radiation therapy, for which the authors detail a number of clinical trials in progress, is its immunomodulatory role, with or without systemic therapy agents, in the treatment of patients with kidney cancer. Multimodal therapy for renal cancer, including radiation therapy, may be important. Our field needs to design the appropriate trials to prove it.

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

 Siva S, Louie AV, Warner A, et al. Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: a report from the International Radiosurgery Oncology Consortium for Kidney (IROCK). Cancer. 2018;124:934-42.

 Turajlic S, Xu H, Litchfield K, et al; PEACE; TRACERx Renal Consortium. Tracking cancer evolution reveals constrained routes to metastases: TRACERx Renal. Cell. 2018;173:581-94.e12.

Dr. Master is a Professor, Associate Chair for Clinical Affairs and Quality, and Director of the Clinical Research Unit in the Department of Urology at Emory University in Atlanta, Georgia.

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 Cochran DC, Chan MD, Aklilu M, et al. The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery. J Neurosurg. 2012;116:978-83.

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 Staehler M, Haseke N, Nuhn P, et al. Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma. BJU Int. 2011;108:673-8.

 Kothari G, Foroudi F, Gill S, et al. Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: a systematic review. Acta Oncol. 2015;54:148-57.

 Balagamwala EH, Angelov L, Koyfman SA, et al. Single-fraction stereotactic body radiotherapy for spinal metastases from renal cell carcinoma. J Neurosurg Spine. 2012;17:556-64.

 Jhaveri PM, Teh BS, Paulino AC, et al. A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases. Acta Oncol. 2012;51:584-8.

 Zelefsky MJ, Greco C, Motzer R, et al. Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Int J Radiat Oncol Biol Phys. 2012;82:1744-8.

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 Teh B, Bloch C, Galli-Guevara M, et al. The treatment of primary and metastatic renal cell carcinoma (RCC) with image-guided stereotactic body radiation therapy (SBRT). Biomed Imaging Interv J. 2007;3:e6.

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Articles

This review summarizes the current evidence supporting the use of SBRT as treatment for inoperable renal cell carcinoma, as well as provides recommendations for patient selection and reviews the technical aspects of treatment and the expected toxicities.

When Surgery Is Not an Option in Renal Cell Carcinoma: The Evolving Role of Stereotactic Body Radiation Therapy

Survivors of childhood and young adult cancer are at risk for developing subsequent malignant neoplasms, including lung cancer. As survival rates in this group continue to improve and patients enter later decades in life, determining the optimal surveillance and counseling strategies with regards to subsequent cancers remains a challenge. In this case report, we present a non-Hodgkin lymphoma survivor who was incidentally found to have non–small-cell lung cancer 30 years after undergoing treatment that included mantle radiation. We discuss the treatment-related risk factors for lung cancer in this population and potential implications for long-term follow-up.

As a result of improving treatment and supportive care, the population of childhood and young adult cancer survivors is expected to continue to rise over the coming years.[1] Childhood and young adult cancer survivors are at increased risk for a multitude of adverse late effects, including subsequent malignant neoplasms.[2-5] The historical mainstay for treatment of non-Hodgkin lymphoma has been chemotherapy with or without radiation therapy (RT); both alkylating chemotherapy and RT have been associated with the development of subsequent malignant neoplasms, including malignancies of the skin, breast, thyroid, gastrointestinal tract, and lung.[2, 6-12]

In the general population, results from the National Lung Screening Trial (NLST) indicate that surveillance for lung cancer among smokers who are at high risk confers a mortality benefit.[13] What remains unclear is what the optimal lung cancer surveillance strategy is for childhood and young adult survivors who received RT to the lung fields. In the absence of a large definitive randomized controlled trial directly investigating this question, clinicians taking care of these survivors must rely on retrospective epidemiological studies, registry data, and statistical modeling where available. The aim of this paper is to describe a case of non–small-cell lung cancer (NSCLC) following mantle RT for non-Hodgkin lymphoma and to briefly review the epidemiology of lung cancer in childhood and young adult cancer survivors, with the goal of assisting the clinician in thinking about lung cancer risk in this population.

A 61-year-old woman who was a survivor of non-Hodgkin lymphoma was referred for abdominal CT by her outside gynecologist for a chief complaint of left flank pain. An 8-mm left pulmonary nodule was incidentally noted in the left lower lobe. A repeat scan showed no growth in the nodule 2 months later. However, a subsequent scan 8 months after the first demonstrated interval growth of the nodule to a size of 14 × 11 mm. At that point, she was referred to thoracic surgery for biopsy and definitive treatment.

Her previous medical history was significant for non-Hodgkin lymphoma diagnosed at age 30, for which she received cyclophosphamide, vincristine, prednisone, methotrexate, doxorubicin, mercaptopurine, carmustine, and L-asparaginase. She also underwent mantle and pericardial irradiation (total dose, 35 Gy). At her annual survivorship appointment, her other medical problems were noted to be hypothyroidism and hyperlipidemia. She had no history of tobacco, alcohol, or drug use, and she denied environmental exposures, including to asbestos.

To evaluate her pulmonary nodule, she underwent a PET scan, which showed increased 18F-fluorodeoxyglucose (FDG) uptake, raising suspicion for lung neoplasm. A fine needle aspiration biopsy of the left lung nodule revealed lung adenocarcinoma. She underwent a left lower lobe anterior segmentectomy and mediastinal lymph node dissection. After an uneventful recovery from surgery, she was followed with periodic re-imaging. Pathology of the nodule confirmed a diagnosis of stage IA NSCLC (T1aN0m0). She has remained disease-free for longer than 3 years after surgery.

We performed a brief review of the English language literature using PubMed from inception to March 12 of this year, with combinations of the search terms "childhood cancer," "lymphoma," "survivor," "lung cancer," and "subsequent neoplasm,"Â as well as their derivatives. Bibliographies of literature identified by our search strategy were also hand searched for additional relevant articles and reviews of this population. Case reports, case series, institutional experiences, registry studies, and reviews discussing the incidence and clinical characteristics of lung cancers diagnosed in childhood and young adult survivors were all included. Studies not commenting on lung cancer specifically were excluded.

In our report, we describe the case of a female non-Hodgkin lymphoma survivor who at age 61 had an incidental finding on imaging that was later revealed to be NSCLC. Given the absence of any identifiable environmental exposures, our case raises the concern that her earlier treatment with mantle RT contributed to her lung cancer risk. In addition, her disease-free survival 3 years after surgical resection illustrates the potential benefit of an early diagnosis and raises the question of whether other survivors with a history of RT to fields including the lungs would benefit from a CT-based lung cancer detection program.

In the cancer survivor population, the development of malignancies after RT is well-recognized, but heterogeneity in risk factors (including primary tumor biology, age at treatment, duration of follow-up, environmental exposures, and hereditary predisposition) has made attempts to estimate attributable risk difficult.[14] In a 2009 study on the Childhood Cancer Survivor Study (CCSS) cohort, the 20-year overall cumulative incidence of subsequent malignant neoplasms in 14,358 5-year childhood cancer survivors was estimated to be approximately 3% to 4%.[15] This group included patients treated for leukemia, lymphoma, neuroblastoma, soft-tissue sarcoma, bone cancer, central nervous system cancer, or Wilms tumor. Of these patients, 67% received RT, which was identified as a significant risk factor. Using Surveillance, Epidemiology, and End Results (SEER) Program cancer registries, Inskip et al reported a similar pattern of epidemiology in subsequent malignant neoplasms, including 7 cases of lung cancer among a cohort of 25,965 2-month survivors of childhood cancer.[16] Though the absolute number of cases was small, the expected number of lung cancers in this age group was even smaller, resulting in an observed-to-expected ratio (O/E) of 7.4 (

 < .05). Importantly, survivors with a history of RT had an O/E ratio for cancers of the lung and bronchus of 17.0 (

 < .05), while those without a history of RT had an O/E ratio of 5.4 (not significant).[16]

A 2011 meta-analysis of 23 studies by Pirani et al sought to investigate the overall risk for secondary malignancies in non-Hodgkin lymphoma survivors; pooling the results of 12 studies, the lifetime risk of developing lung cancer after non-Hodgkin lymphoma was 1.53 (233,293 total patients; 95% CI, 1.36-1.73) compared with controls without a history of the disease.[17] A 2013 meta-analysis of 21 studies by Ibrahim et al estimated that the cumulative incidence of lung cancer at 20-year follow-up after treatment for Hodgkin lymphoma ranged from 0.1% to 6.2%,[18] with a mean latency of 11.5 years between primary treatment and development of lung cancer.[19] A pooled analysis of German cancer registry data estimated that the standardized incidence ratio for lung cancer in non-Hodgkin lymphoma survivors was 2.08 (95% CI, 1.84-2.33); in Hodgkin lymphoma survivors, it was 3.64 (95% CI, 2.9-4.47).[20]

Higher treatment doses with radiation appear to impart a higher risk for lung cancer, as illustrated in an institutional retrospective study by Almagro-Casado et al in 2016.[19] Exposure to RT was associated with solid neoplasm development in these survivors, with an increased risk for lung cancer (hazard ratio, 4.0; 95% CI, 1.1-11.6) in patients receiving RT doses greater than 42 Gy compared with patients receiving less than 42 Gy. The median overall survival (OS) after lung cancer diagnosis was 12.6 months. However, patients diagnosed incidentally prior to the onset of symptoms had more favorable staging and better prognoses compared with patients who had been diagnosed after the onset of symptoms (median OS, 49.1 months vs 5.9 months).

It remains unclear to what extent underlying biological or genetic factors in the non-Hodgkin lymphoma survivor population could contribute to the risk of subsequent lung cancer. Friedman et al noted a statistically significant increase overall in the risk of malignancy (standardized incidence ratio [SIR], 1.8; 95% CI, 1.3-2.5) in siblings of patients with non-Hodgkin lymphoma compared with the general population, suggesting a genetic or environmental component[21]; notably, however, no increased risk for lung cancer was noted in siblings (SIR, 1.3; 95% CI, 0.6-2.9). Similarly, in a study by Landgren et al, non-Hodgkin lymphoma survivors with a positive family history of cancer did not have a statistically significant increased risk of developing lung cancer compared with similar survivors without a family history of cancer (risk ratio, 1.99; 95% CI, 0.73-5.39).[22]

A 2018 paper by Holmqvist et al sought to investigate the risk of subsequent malignant neoplasms after treatment for childhood Hodgkin lymphoma; they examined a cohort of 1,136 patients with Hodgkin lymphoma who were treated before age 17 between 1955 and 1986.[23] The cumulative incidence of lung cancer was 2.3% by age 50 years, though the highest at risk were men treated with chest RT at age < 10 years, with a cumulative incidence of 4.2% by age 50 years; indeed, 10 of the 11 lung cancer cases they identified were in men, and were diagnosed a median of 28 years after Hodgkin lymphoma. When compared with the general population, male survivors had an SIR of 26.7, whereas the SIR for women was 3.3 (95% CI, 0.2-14.6). Notably, all 11 lung cancer cases developed in patients who had received chest RT.

A limitation voiced by most investigators in these retrospective studies is that patient smoking status is commonly unavailable, but is suspected to contribute significantly to lung cancer risk in lymphoma survivors.[17-20] The male predominance (76%) of lung cancer cases has been speculated to be due to historical differences in tobacco use between men and women.[18,24] A synergistic mechanism between radiation exposure and smoking is suggested,[19,23] and highlights the need to address smoking status with cancer survivors.

Another ongoing area of investigation is on how the risk of lung cancer changes over time as survivors age.[14] Early reports from the CCSS cohort reported few cases of lung cancer: in fact, none were reported in their 2001 paper (median age, 23 years; range, 8-47 years)[25]; 4 cases were reported in the 2006 paper, of which 3 were Hodgkin lymphoma survivors.[26] Though few in number, these cases represented an elevated risk compared with the general population (overall SIR, 3.1; 95% CI, 1.2-8.2).[26] A CCSS report in 2015 by Turcotte et al that investigated subsequent malignant neoplasm incidence during the fifth and sixth decades of life showed that most of the lung cancers they identified occurred after age 40 (5 cases after age 40, 1 case before; all cases had received radiation).[27] Of note, no excess risk for lung cancer was identified compared with the general population; this finding was speculated to be due to the risk of lung cancer also increasing in the general population in later decades of life, which would mitigate the difference in risk between the two groups.

The NLST demonstrated a mortality benefit from screening high-risk patients (age, 55-74 years, with at least a 30 pack-year tobacco history) with low-dose CT compared with chest radiography.[13] Patients screened with low-dose CT had earlier staging and fewer deaths compared with those screened with chest radiography. The results of this trial impacted guidelines, with multiple expert groups recommending the incorporation of lung cancer screening with low-dose CT in patients at high risk.[28-30] The current Children's Oncology Group guidelines recommend that survivors exposed to chest or axillary radiation during treatment be counseled on the potential benefits and harms of spiral CT scanning for patients at highest risk.[31] Risks of spiral CT scanning in this setting include the possibility of a false-positive finding, which could result in patient distress, biopsy-associated morbidity, and unnecessary surgery. In the NLST, the rate of false-positive findings was very high in both screening groups (96.1% for CT, 93.9% for chest x-ray).[13] Other important questions that remain are: What is the radiation dose threshold that should be used to identify patients at highest risk? Should there be an optional screening interval? And, how do we incorporate the possible interaction between RT and tobacco use into screening decisions?

In any patient, the news of a cancer diagnosis can be devastating; however, as our case demonstrates, diagnosis at an early stage can result in a favorable outcome. Current survivorship guidelines do not recommend lung cancer surveillance based on a history of RT or chemotherapy. Yet, these exposures are likely relevant to risk.

At this time, the existing evidence does not appear to support a role for a CT-based lung cancer detection program among survivors who never smoked. Whether the demonstrated benefit of a CT-based lung cancer detection program can be applied to childhood and young adult cancer survivors without a history of smoking or to other survivors who have received radiation to the lungs is unknown.[13] Future studies that include modeling of surveillance strategies may be helpful. Regardless of their baseline risk or exposure to radiation, all patients should be counseled on smoking cessation.

This work was supported by the Meg BertÃ© Owen Fund and the National Institutes of Health (P30 CA008748)

 Noone A, Howlander N, Krapcho M, et al (editors). SEER Cancer Statistic Review, 1975-2015. Bethesda, MD: National Cancer Institute, 2018.

 Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102:1083-95.

 Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572-82.

 Geenen MM, Cardous-Ubbink MC, Kremer LC, et al. Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA. 2007;297:2705-15.

 Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2328-38.

 Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med. 1996;334:745-51.

 Metayer C, Lynch CF, Clarke EA, et al. Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol. 2000;18:2435-43.

 Maule M, Scelo G, Pastore G, et al. Risk of second malignant neoplasms after childhood leukemia and lymphoma: an international study. J Natl Cancer Inst. 2007;99:790-800.

 Turcotte LM, Liu Q, Yasui Y, et al. Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. JAMA. 2017;317:814-24.

 Berrington de Gonzalez A, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys. 2013;86:224-33.

 Turcotte LM, Neglia JP, Reulen RC, et al. Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review. J Clin Oncol. 2018;36:2145-52.

 Morton LM, Dores GM, Curtis RE, et al. Stomach cancer risk after treatment for Hodgkin lymphoma. J Clin Oncol. 2013;31:3369-77.

 National Lung Screening Trial Research Team, Church TR, Black WC, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368:1980-91.

 Ng AK, Kenney LB, Gilbert ES, Travis LB. Secondary malignancies across the age spectrum. Semin Radiat Oncol. 2010;20:67-78.

 Meadows AT, Friedman DL, Neglia JP, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009;27:2356-62.

 Inskip PD, Curtis RE. New malignancies following childhood cancer in the United States, 1973-2002. Int J Cancer. 2007;121:2233-40.

 Pirani M, Marcheselli R, Marcheselli L, et al. Risk for second malignancies in non-Hodgkin's lymphoma survivors: a meta-analysis. Ann Oncol. 2011;22:1845-58.

 Ibrahim EM, Kazkaz GA, Abouelkhair KM, et al. Increased risk of second lung cancer in Hodgkin's lymphoma survivors: a meta-analysis. Lung. 2013;191:117-34.

 Almagro-Casado E, Sanchez A, Cantos B, et al. Lung cancer and other second neoplasms after treatment of Hodgkin lymphoma. Clin Transl Oncol. 2016;18:99-106.

 Baras N, Dahm S, Haberland J, et al. Subsequent malignancies among long-term survivors of Hodgkin lymphoma and non-Hodgkin lymphoma: a pooled analysis of German cancer registry data (1990-2012). Br J Haematol. 2017;177:226-42.

 Friedman DL, Kadan-Lottick NS, Whitton J, et al. Increased risk of cancer among siblings of long-term childhood cancer survivors: a report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev. 2005;14:1922-7.

 Landgren O, Pfeiffer RM, Stewart L, et al. Risk of second malignant neoplasms among lymphoma patients with a family history of cancer. Int J Cancer. 2007;120:1099-102.

 Holmqvist AS, Chen Y, Berano Teh J, et al. Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-identification of high-risk populations to guide surveillance: a report from the Late Effects Study Group. Cancer. 2019;125:1373-83.

 Weiss W. Cigarette smoking and lung cancer trends: a light at the end of the tunnel? Chest. 1997;111:1414-6.

 Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst. 2001;93:618-29.

 Bassal M, Mertens AC, Taylor L, et al. Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006;24:476-83.

 Turcotte LM, Whitton JA, Friedman DL, et al. Risk of subsequent neoplasms during the fifth and sixth decades of life in the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2015;33:3568-75.

 de Koning HJ, Meza R, Plevritis SK, et al. Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the US Preventive Services Task Force. Ann Intern Med. 2014;160:311-20.

 Jaklitsch MT, Jacobson FL, Austin JH, et al. The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg. 2012;144:33-8.

 Wood DE. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for lung cancer screening. Thorac Surg Clin. 2015;25:185-97.

 Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers, version 5.0. 

In this case report, we present a non-Hodgkin lymphoma survivor who was incidentally found to have non–small-cell lung cancer 30 years after undergoing treatment that included mantle radiation. We discuss the treatment-related risk factors for lung cancer in this population and potential implications for long-term follow-up.

Non–Small-Cell Lung Cancer After Mantle Radiation: A Case Report and Brief Review

 spoke with the lead investigator of the ATOMIC trial (ClinicalTrials.gov identifier: NCT02912559), Frank A. Sinicrope, MD, about utilizing immunotherapy in the adjuvant setting for colon cancer based on its impressive results in a subset of metastatic colorectal cancers.

First, what immunotherapy agents are currently used in patients with colorectal cancer?

: Currently, the use of immunotherapy in the treatment of colorectal cancer is restricted to a subset of metastatic tumors (~5%) that show deficiency in DNA mismatch repair.[1-3] These tumors have a defect in the ability to repair nucleotide mismatches in DNA, which results in microsatellite instability (MSI). MSI tumors are genetically unstable and carry numerous mutations that trigger the expression of neoantigens, which serve to attract abundant lymphocytes into the tumor. These “inflamed” tumors have been shown to respond favorably and, in some cases, dramatically to immune checkpoint inhibitors. The US Food and Drug Administration (FDA) has approved the use of immune checkpoint inhibitors for only those with metastatic colorectal cancers with MSI. Currently approved treatments include the anti–programmed death 1 (PD-1) antibodies pembrolizumab and nivolumab given as monotherapy, as well as the combination of nivolumab plus low-dose ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody.[1-3] Importantly, pembrolizumab was approved for the treatment of patients with any type of solid tumor with MSI, so it's not restricted to colorectal cancer. The combination of nivolumab and ipilimumab was shown to produce a higher response rate and better outcomes[3] when indirectly compared with nivolumab monotherapy from another study, and was associated with increased but manageable toxicities. Despite impressive results with these immunotherapy agents, it is important to note that only half of patients with metastatic disease demonstrate durable responses; therefore, studies to identify and circumvent resistant mechanisms are ongoing.

There are completed and multiple ongoing clinical trials to determine if the much larger group of non-MSI, or microsatellite stable, metastatic colorectal cancers might also benefit from immunotherapy, but thus far most of these studies have been negative. However, various strategies are being tested to see if we can increase the extent of inflammation within the tumor to better sensitize them to immunotherapy drugs.

Can you tell us about the design of this new phase III trial that you are leading, including which patients are eligible?

: The ATOMIC trial is looking to see if immunotherapy that has been effective in metastatic colon cancers with MSI due to DNA mismatch repair deficiency can be applied to earlier-stage disease, specifically nonmetastatic stage III colon cancer. Currently, the standard of care after surgical resection for stage III colon cancers is chemotherapy for 3 or 6 months, depending on risk grouping determined by T and N stage data. Adjuvant therapy, including immunotherapy for patients following surgical removal of their tumor, is directed towards eradicating micrometastases. This strategy using immunotherapy has been successful in patients with stage III melanoma, in which an immune checkpoint inhibitor was effective in reducing recurrence and death. So, we are using a similar tactic but selecting for patients with hypermutated colon cancer and applying this strategy to earlier-stage, nonmetastatic disease.

The ATOMIC trial is evaluating the standard chemotherapy regimen FOLFOX, which is a combination of fluorouracil, leucovorin, and oxaliplatin, and randomizing patients to either this regimen alone for 6 months or to this regimen combined with the anti–programmed death ligand 1 (PD-L1) immune checkpoint antibody atezolizumab. Atezolizumab is given together with this chemotherapy for 6 months and then is continued as monotherapy for an additional 6 months. We are looking to see if atezolizumab will improve the survival of these patients. Again, the study is targeted towards the group of patients whose tumors have MSI due to mismatch repair deficiency.

It's important to point out that it is now standard practice to test all newly diagnosed colon cancer patients for defects in mismatch repair. This is done in pathology laboratories around the country where, typically, the tumor is tested for the expression of four proteins (MLH1, MSH2, MSH6, and PMS2) that govern the DNA mismatch repair system in the cell. A patient's tumor tissue is stained for these proteins and if there is loss of one or more of these proteins, then this provides evidence for an inactivated or mutated gene, which can be a germline or heritable event (Lynch syndrome), or alternatively, inactivation of the 

 gene due to methylation, which is a sporadic event. Approximately 12% of stage III colon cancers show deficient mismatch repair-or MSI. The ATOMIC trial aims to accrue 700 patients total; we currently have 167 patients enrolled on the trial, so we are actively recruiting patients. An interim analysis for efficacy or futility is planned for when 50% of the projected outcome events have occurred.

Q: You mentioned the rationale for taking this immunotherapy strategy into the adjuvant setting. Is there preclinical or early clinical evidence for combining chemotherapy with immunotherapy in colorectal cancer?

 An important yet incompletely understood issue is whether immunotherapy drugs should be given alone or combined with chemotherapy and, if so, in what sequence to achieve the best efficacy. Such an approach will likely need to be tumor type–specific; in colorectal cancer, there are limited data on the combination of chemotherapy plus immunotherapy. At this time, we have seen impressive efficacy for immune checkpoint inhibitors in the subgroup of metastatic colorectal cancers with MSI, but we do not know if the combination of chemotherapy plus immunotherapy is more effective than just giving immunotherapy alone. This issue is being addressed in an ongoing study being conducted by the NRG Cooperative Group in the metastatic setting (ClinicalTrials.gov identifier: NCT02997228). For the ATOMIC trial, patients are being treated with the intent to cure their disease, and adjuvant chemotherapy is of proven benefit and is standard of care. Accordingly, the initial way to study the potential benefit of immunotherapy is to look at its combination with standard chemotherapy and compare that with standard chemotherapy alone. In this way, we do not deprive patients of the chemotherapy that we know is effective in this setting.

Are there other similar trials that are also testing novel adjuvant approaches for colorectal cancer that you could highlight?

 The ATOMIC study is the only adjuvant trial in the United States that is currently looking at immunotherapy for the treatment of stage III colon cancer. There are ongoing discussions about evaluating molecularly targeted agents as adjuvant therapy for colon cancer, particularly for tumors with 

 V600E mutations that are associated with worse prognosis in these patients. The ATOMIC study has the potential to be practice-changing in that it will determine whether immunotherapy is an effective treatment for the subset of colon cancers with MSI, where it has the best chance of being effective.

It is important to emphasize that immunotherapy has not been shown to benefit the majority of patients with colorectal cancer who do not have hypermutated tumors. Colorectal cancer is lagging behind some of the other tumor types in which immunotherapy has shown efficacy for a larger proportion of ptients. This is a very active area of research, to understand the factors that determine both the likelihood of response and the mechanisms underlying treatment resistance, such that we can overcome them so that more patients can receive and benefit from this remarkable new treatment.

Dr. Sinicrope is a consultant to Roche/Ventana Medical Systems, which has products for mismatch repair testing.

Immunotherapy Promising for Metastatic MSI-H/dMMR Colorectal Cancer

Harnessing the immune system of a patient to fight his or her own cancer has been studied for many years. A breakthrough in immunotherapy that revolutionized the oncology field was achieved only after the discovery of a means to modulate immune checkpoints: via a pathway that enables tumor cells to display a cell-surface profile that resembles that of their normal counterparts, despite their differences, therefore evading antitumor immunity.

In 2017, the US Food and Drug Administration approved pembrolizumab, a checkpoint inhibitor that targets the programmed death 1 pathway, as a second-line treatment for all metastatic solid tumor types classified as microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR), including this type of colorectal cancer.

In the United States, colorectal cancer is the third most common diagnosed cancer type, and the second deadliest, in both men and women. However, only a small subset of colorectal cancer patients with metastatic disease have tumors with MSI-H or dMMR characteristics and are candidates for immunotherapy. Only those patients with Lynch syndrome, and those who randomly acquire alterations in one of the MMR genes, are eligible for immunotherapy.

In this interview, Dr. Sinicrope nicely summarizes the background, successes, and challenges of immunotherapy for the treatment of colorectal cancer. As the lead investigator of the phase III ATOMIC trial (ClinicalTrials.gov identifier: NCT02912559), he explains how this research builds on very positive survival data seen with immunotherapy in metastatic MSI-H/dMMR colorectal cancer, and aims to expand the utilization of immunotherapy for additional colorectal cancer patients.

While the trial is still restricted to MSI-H/dMMR colorectal cancer patients, it is set to determine whether patients diagnosed with stage III colorectal cancer would benefit from the combination of atezolizumab with the current standard of care, defined as surgery and an adjuvant chemotherapy regimen of folinic acid, fluorouracil, and oxaliplatin (FOLFOX).

The ATOMIC trial is the only ongoing immunotherapy trial in stage III colorectal cancer patients. If successful, recurrence and death in stage III colorectal cancer patients with MSI would be reduced. Therefore, testing all patients for MSI is of interest, not only to increase patients' eligibility for the trial, but also to raise awareness about Lynch syndrome and family medical history of this condition. A positive trial outcome may ultimately open the door for additional studies, such as those focusing on whether the efficacy of immune checkpoint inhibitors could be extended as a single agent for MSI-H/dMMR tumors.

Finally, multiple ongoing studies are investigating the expansion of immunotherapy beyond immune checkpoint inhibitors in MSI-H/dMMR tumors to the broader population of colorectal cancer patients.

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

Dr. Yarden is Director of Medical Affairs for the not-for-profit Colorectal Cancer Alliance, and former Assistant Professor and Researcher at Georgetown University, both in Washington, DC.

 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-13.

 Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182-91.

 Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-9.

Dr. Sinicrope reviews the phase III ATOMIC trial, which is testing standard chemotherapy alone or in combination with the anti–PD-L1 antibody atezolizumab as adjuvant therapy in a subset of colon cancer patients.

Evaluating Immunotherapy in Nonmetastatic Colorectal Cancer

Cancer, the second leading cause of death globally, remains a significant challenge for societies, healthcare systems, and affected individuals worldwide. Adding to this challenge are complex disparities in access to and use of cancer care, basic and clinical research, and clinical trials, as well as disparities in cultural beliefs and genetics. To improve cancer treatment, it is essential that cancer investigators, cooperative groups, national research institutions, national governments, competent authorities, ethics committees, and pharmaceutical companies come together to strengthen global collaboration in cancer research. Once we reach this goal, the resulting data will be more broadly applicable to all patients. This article reviews the current state of cancer research around the world.

Cancer is a significant challenge for society, healthcare systems, and the growing number of affected patients and their families. In 2018, out of the 18 million cases of cancer worldwide, 9.5 million were in men and 8.5 million were in women. Cancer is the second leading cause of death globally, with an estimated 9.6 million deaths.[1] The most common cancers are lung cancer (2.09 million), female breast cancer (2.09 million), prostate cancer (1.28 million), colorectal cancer (1.1 million), non-melanoma skin malignancies (1.04 million), and stomach cancer (1.03 million). Cancer-related deaths, from most to least frequent, are due to lung cancer (1.76 million), colorectal cancer (862,000), stomach cancer (783,000), and liver cancer (782,000). More than two-thirds of these cancer fatalities occur in low- and middle-income countries.[2]

High body mass index, low fruit and vegetable consumption, lack of physical activity, tobacco use, and alcohol use are the five leading behavioral and dietary risk factors for cancer-related deaths. It is estimated that tobacco use alone is responsible for approximately 22% of cancer deaths.[3] Some 25% of cancer cases in low- and middle-income countries stem from infections, such as hepatitis and human papillomavirus.[4] Beyond the risk factors and common causes of cancer, the economic impact of the disease is significant, and it is increasing. More than 90% of high-income countries have cancer treatment services available compared with fewer than 30% of low-income countries. Only one in five low- and middle-income countries has the necessary data to drive cancer policy.[5,6]

No single country can successfully fight this global public health problem on its own. Science is collaborative in nature and international in scope. To effectively improve treatments and identify cures, it is essential to fund the most promising research from all corners of the globe. Translational cancer research covers the continuum of research, including basic, preclinical, early clinical, late clinical, and outcomes research. Basic/preclinical research serves as the foundation for early clinical research, bridging the gap between science and practice. A prime example comes in the form of progress made towards controlling the infectious diseases that are linked to certain malignancies, such as hepatocellular carcinoma, cervical cancer, and stomach cancer. Coordinated approaches in basic research, translational research, and clinical trials may be applied to fighting cancer worldwide. This article reviews the current state of cancer research around the globe.

Cancer Research in the United States and Canada

While 85% of cancer patients are diagnosed and treated at local, community-based clinical practices, cancer-related clinical research and clinical trials have traditionally been conducted at well-established academic medical centers in the United States. For the last 4 decades, the National Cancer Institute (NCI) has acknowledged the importance of community-based oncology research through several initiatives and programs. The significance of this research was validated in 1982, when the NCI initiated the Community Clinical Oncology Program (CCOP).[7] The CCOP was designed to disseminate and implement advances in cancer care by linking cancer investigators and academic centers to community-based practices, thus expanding access to clinical trials and promoting cancer treatment innovations within the community populations that otherwise might not have had access. This collaborative partnership between research institutions and community physicians helped to facilitate phase III cancer prevention, control, and treatment trials in the local practice setting. Despite these efforts, community-based cancer research continued to face challenges as a result of the era of emerging science, technology, genomics, and molecularly targeted therapy, as well as a rapidly changing healthcare environment.

In 2007, the NCI further expanded its community-based efforts by launching the NCI Community Cancer Centers Programs (NCCCP), a publicÃ¢€“private partnership with 21 community hospitals in 16 states.[8] The goals of the NCCCP were to enhance access to, and improve the quality of, cancer care by expanding the infrastructure to support a platform for basic, clinical, and population-based research, as well as informatics, biospecimen collection, and cancer care disparities in community hospitals. Self-reported data from NCCCP sites between 2007 and 2010, supplemented with data from the NCI Cancer Therapy Evaluation Program, showed that the availability of phase III trials and patient accrual increased by 16% and 133%, respectively, at NCCCP sites, compared with 8% and 30% nationally. In addition, enrollment of racial and ethnic minorities in oncology trials increased by 82%, from 83 to 151 patients; the accrual of patients age 65 years or older in oncology trials also rose by 221%, from 200 to 641 patients at NCCCP sites. The exact changes in trial portfolios and accrual differed by sophistication of the site and by prior experience conducting clinical trials at the site.[9]

In 2014, the NCI initiated a new community-based program, the NCI Community Oncology Research Program (NCORP), to align with and replace the CCOP and NCCCP programs. The goals of the NCORP are to support clinical trials on cancer control, prevention, treatment, and cancer screening in the community setting, as well as to expand the scope of research to include cancer care delivery. The NCORP initiative emerged around the same time as two other significant changes: 1) the transformation and condensing of nine longstanding NCI Cooperative Group Programs into four new groups under the National Clinical Trials Network (NCTN), and 2) the implementation of the NCI Central Institutional Review Board. Both of these changes helped to provide easier access to all NCI Cooperative Group clinical trials, with some reduced regulatory load.

The NCTN structure included five US Network groups and the Canadian Collaborating Clinical Trials Network (

). Membership in the individual NCTN groups is based on criteria that are specific to each group. Sites can belong to more than one group, and membership in at least one group allows a site to participate in the trials led by any NCTN group for which their investigators are qualified. Consequently, researchers from the Lead Academic Participating Sites, NCORP, other academic centers, community practices, and international members associated with the Network groups may all enroll patients onto NCTN trials. Clinical trials led by NCTN groups may receive support from the Imaging and Radiation Oncology Core Group, Clinical and Translational Science Awards, and tissue banks, according to the scientific needs of the trials.

The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) is the adult cooperative oncology group based in Canada committed to assessing all modalities of therapy across the spectrum of different types of cancer. The NCIC-CTG has been operational since 1980.[10] The group's activities have included leadership of, and participation in, large randomized clinical trials conducted in the United States and Canada by both the NCIC-CTG and US-based cooperative groups. The mission of the NCIC-CTG is to develop and conduct clinical trials aimed at improving the treatment and prevention of cancer, with the ultimate goal of reducing morbidity and mortality from this disease. NCIC-CTG collaborates with the NCI's Cancer Therapy Evaluation Program and US-based groups through its NCTN Program to develop new intergroup trials under NCIC-CTG leadership and to ensure more rapid accrual to trials led by US-based groups, thereby enhancing the overall clinical research program for adults and children with cancer.

Pharmaceutical companies may run international trials on their own or in conjunction with established clinical trials cooperative groups. Untill the late 1990s, few pharmaceutical companies showed interest in oncology products. Most new anticancer drugs in development reached the cooperative group researchers through the NCI. Within the past 2 decades, however, a record number of pharmaceutical and biotechnology companies have come up with hundreds of novel agents, compelling cooperative group investigators to work directly with industry partners. Chronic underfunding of the cooperative groups by NCI, coupled with the opportunity to access novel compounds, inevitably led to the development of much closer relationships between the cooperative groups and the pharmaceutical industry. While some effective collaborations between industry and clinical trials groups have resulted in the successful completion of many important cancer trials, the potential conflict between the goals of government-funded cooperative groups vs pharmaceutical industry sponsors has raised concerns in some others. The primary objective of the pharmaceutical companies is to provide data appropriate for a licensing application, while the objective of the cooperative groups is to evaluate the additive benefit of that new agent to standard treatment. A trial addressing a question of great importance to oncologists and patients may be of no interest to the pharmaceutical industry. The cooperative groups may also want to combine or compare agents from two different companies, which may not serve the interests of industry.[11] This is an ongoing challenge in the United States especially.

While representing less than 10% of the global population, one-quarter of all cancers occur in Europe. Due to an aging population, these numbers are expected to increase, with an estimated 3.9 million Europeans diagnosed with cancer and 2 million cancer-related deaths in 2018 alone. Progress from basic research to patient treatment has historically been a long and fragmented process in Europe. At the 2000 European Council meeting in Lisbon, member states of the European Union signed on to an ambitious program aimed at helping Europe to become the most competitive and dynamic knowledge-based economy in the world by 2010. The cornerstone of the Lisbon Agenda was the creation of a European Research Area.[12] These activities led to the establishment of the European Research Council in 2007, which helped consolidate fragmented European research towards innovation.[13-15] A pivotal Sixth Framework Programme initiative, the EUROCAN+PLUS Project, was followed by the Seventh Framework Programme EurocanPlatform Network of Excellence in 2011, emphasizing the need to stimulate multisite translational cancer research policies.

A direct outcome of these projects was the formation of Cancer Core Europe (CCE) in 2014. The main goal of CCE is to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations. Cancer Core Europe is now a legal entity including seven large European cancer centers, most of which are Comprehensive Cancer Centers. They operate with a single portal system to engage in various research projects with partners. Motivated by the creation of CCE, the leaders of 10 research institutes with prominent cancer prevention programs in Europe (the International Agency for Research on Cancer in France, and institutes in the United Kingdom, Denmark, Netherlands, Germany, Sweden, and Italy) came together and established Cancer Prevention Europe (CPE).[16]

CPE is a consortium of multidisciplinary centers focused on reducing cancer mortality and morbidity through development of prevention policies. These infrastructures are intended to serve as a hub to connect and interact with other centers across Europe and beyond, bringing innovative approaches to cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes. Presently, CCE and CPE are integrating therapeutics and prevention strategies to address worsening cancer burden as a central engine. In 2017, a goal of achieving long-term survival in 3 out of 4 cancer patients by 2030 was proposed as a mission. This was deemed to be possible through innovative prevention and treatment strategies in a virtual European cancer center/infrastructure.[17] In June 2018, a press release from the European Commission concerning Horizon Europe stated that "Examples of missions could range from the fight against cancer, to clean transport or plastic free oceans."[18]

Cancer Research in the Asia-Pacific Region

Cancer is one of the leading causes of death in South Korea, Taiwan, Singapore, and Hong Kong, as well as in urban China. The incidence of cancer has increased significantly over the past several years in the Asia-Pacific region, becoming a major concern for many healthcare systems. During the 1980s and 1990s, impressive economic growth in the East and Southeast Asia countries and China has improved standards of living and healthcare systems, leading to fewer deaths from infectious diseases. The increase in cancer deaths has been attributed to the enormous economic successes, longer life spans, and a population that is expanding far more rapidly than those in Europe and the United States. Furthermore, the proportion of people older than 65 years of age has been increasing. Over the last 25 years, while the total population of China has increased by 31%, the number of people over age 65 years has increased by 81%.[19,20]

The number of cancer cases in Asia is expected to rise to 8.1 million by 2020 if the current management strategies are not changed. Much of the Asia-Pacific population has certain characteristics that increase their cancer risk. In men, the smoking rate is about twice that seen in Europe and the United States. Culprit infections are much more common in Southeast Asia, including 

, which increases the risk of stomach cancer by 5 to 6 times, and hepatitis B, which increases the risk of liver cancer. Nasopharyngeal cancer is a very common disease in Asia, predominantly affecting people of southern Chinese descent. The global UV index for Asia is about twice that of the countries in the Northern Hemisphere, further increasing cancer risk in this population.[21]

While cancer research is in great demand across the Asia-Pacific region, the infrastructure and resources to conduct clinical trials can be variable. Australia, Japan, South Korea, Hong Kong, Taiwan, and Singapore have adequate resources to conduct clinical trials efficiently. Countries such as China and India have built institutions that can provide infrastructure and access to clinical trials for large populations of cancer patients, which has been a good resource for industry clinical trials. With the advent of immuno-oncology and the number of new agents undergoing testing, a multitude of centers and studies have cropped up to meet demands in the region. Challenges to participation in clinical trials in the Asia-Pacific region include specific inclusion/exclusion criteria of these trials, unavailability or irrelevance of the standard care arm (if a trial has one), and the lack of genetic biomarker testing in these developing countries. Another challenge, which at times can be an advantage in the Asia-Pacific region, is the genetic makeup of this population, which may display a difference in the incidence of the mutation being studied.[22]

Similar to the incidence of the most common cancers worldwide, breast cancer, lung cancer, colorectal cancer, and prostate cancer are the most frequent cancers in the Middle Eastern and North African countries. Bladder and stomach cancers, however, constitute the fifth and sixth most common cancers in this region.[23] Cancer incidence rates vary widely within and between Arab populations. There are few population-based cancer registries in Arab countries, with only 2% to 5% of populations reporting high-quality incidence data. National and regional spending on research and development has been relatively modest. In 2013, the regional gross expenditure on research and development by all Arab states was $15.5 million, compared with $282 million and $427 million by the European Union and North America, respectively.[24]

Conducting research in this region of the world has been more challenging due to language barriers and lack of research infrastructure for reliable and valid data collection, as well as too few researchers and too little networking among them.[25] Furthermore, constant political instability in this part of the world has adversely affected the number of research publications in circulation.[25-28] Due to weak infrastructure, low research spending, and the cultural attitudes of physicians and patients towards clinical research, high-evidence analytical research studiesÃ¢€”such as randomized clinical trialsÃ¢€”have been very problematic to conduct.[29-31]

To reduce the incidence and impact of cancer in the Middle East, a regional initiative for cancer research and treatment, the Middle East Cancer Consortium (MECC), was established in 1996. MECC members include the United States, Cyprus, Egypt, Israel, Jordan, the Palestinian Authority, and Turkey.[32-34] The goal of MECC was to launch and sustain academic-based medical programs that bring together scientists, academics, and clinical professionals from its member countries. MECC has helped to establish a successful Middle Eastern Network of Cancer Registry Centers, and initiation of palliative programs in its member countries.

International networks for research collaboration are not new for Europe and North America. The European Organisation for the Research and Treatment of Cancer (EORTC) has been around since 1962, with its top 35 accruing institutions located in 11 European countries, as well as Turkey and Egypt. Likewise, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Children's Oncology Group have brought cancer researchers from Canada and the United States together for many years. The NCIC-CTG has worked closely with investigators in the United States, Europe, and Australia. Advantages of international collaboration include faster accrual for both common and uncommon tumors, broader applicability of research results, fewer duplicative trials, and rapid dissemination of innovations.[35] Thus, the need for global partnership in cancer research is crucial to maximize resource utilization, permitting cancer researchers around the world to complete high-priority trials in a timely manner. There are, however, several challenges to this approach. Regulatory, logistical, and financial hurdles often hamper the conduct of clinical trials even at the individual country level. One can only imagine the hurdles that can be faced when international collaboration is sought. Disadvantages of international collaboration in cancer treatment trials include differing regulations among countries, disparate levels of clinical trial support infrastructure, contrasting processes and schedules for scientific review, longer lead time for concept and trial development, various licensing arrangements and distribution issues for specific drugs, and incongruent contractual issues with pharmaceutical companies in different countries.[35] Despite these challenges, there have been some successful examples of effective international interchange between clinical trials groups. The Breast International Group and the International Breast Cancer Study Group bring together 41 member groups from Europe, Canada, Latin America, Australia/New Zealand, and Asia, in addition to those from North America. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, sponsored by the NCI, the Breast International Group, and GlaxoSmithKline, is an example of a worldwide trial made possible through international collaboration and industry partnership.[36]

With the steady increase in global cancer burden and the unprecedented pace of discoveries in basic cancer science, it is clear that cancer investigators, cooperative groups, national research institutions, national governments, competent authorities, ethics committees, and pharmaceutical companies need to get together, now more than ever, to strengthen global collaboration in cancer research.

Integration of cancer investigators and cooperative groups in Latin America, Asia, Africa, the Middle East, and Europe into the existing cancer research networks is critical if research is to become more representative of the entire globe. Once we reach that goal, the resulting research will be more broadly applicable to all patients.

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

 Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012: Cancer incidence, mortality and prevalence worldwide in 2012 v1.0. IARC CancerBase no. 11. 

http://publications.iarc.fr/Databases/Iarc-Cancerbases/GLOBOCAN-2012-Estimated-Cancer-Incidence-Mortality-And-Prevalence-Worldwide-In-2012-V1.0-2012

 Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.

 GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioral, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Oncol. 2016;388:1659-724.

 Plummer M, de Martel C, Vignat J, et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health. 2016;4:e609-e616.

 World Health Organization International Agency for Research on Cancer. Global Initiative for Cancer Registry Development (GICR). 

 Tangka FK, Subramanian S, Edwards P, et al. Resource requirements for cancer registration in areas with limited resources: Analysis of cost data from four low- and middle-income countries. Cancer Epidemiol. 2016;45(suppl 1):S50-S58.

 Minasian LM, Carpenter WR, Weiner BJ, et al. Translating research into evidence-based practice: the National Cancer Institute Community Clinical Oncology Program. Cancer. 2010;116:4440-9.

 Clauser SB, Johnson MR, O'Brien DM, et al. Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program. Implement Sci. 2009;4:63.

 Hirsch BR, Locke SC, Abernethy AP. Experience of the National Cancer Institute Community Cancer Centers Program on Community-Based Cancer Clinical Trials Activity. J Oncol Pract. 2016;12:e350-e358.

 Meyer RM, Stanton HA, Parulekar WR, et al. Cooperative Group cancer clinical trials: an NCIC Clinical Trials Group perspective. Can Urol Assoc J. 2011;5:379-81.

 Piccart M, Goldhirsch A, Wood W, et al. Keeping faith with trial volunteers. Nature. 2007;446:137-8.

 Planning Agency for the Living Environment. Towards a European Research Area. 

 Celis JE, Gago JM. Shaping science policy in Europe. Mol Oncol. 2014;8:447-57.

 Gannon F. The ERC: from before then to anniversary celebrations. EMBO Rep. 2017;11:1873-4.

This article reviews the current state of cancer research around the world.

Oncology Vol 33 No 5

When Surgery Is Not an Option in Renal Cell Carcinoma: The Evolving Role of Stereotactic Body Radiation Therapy

Non–Small-Cell Lung Cancer After Mantle Radiation: A Case Report and Brief Review

Evaluating Immunotherapy in Nonmetastatic Colorectal Cancer

State of Cancer Research Around the Globe

FDA Approves Two New Indications and Dosage Form for Pembrolizumab

The Role of Primary Tumor Treatment and Metastasis-Directed Therapy in Oligometastatic Prostate Cancer

Hope After Salvage Therapy Fails: Novel Agents for Relapsed/Refractory Hodgkin Lymphoma