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INTRODUCTION — Renal cell carcinomas (RCCs), which originate within the renal cortex, constitute 80 to 85 percent of primary renal neoplasms. Urothelial (transitional cell) carcinomas of the renal pelvis account for approximately 8 percent of kidney tumors, and other parenchymal epithelial tumors, such as oncocytomas, collecting duct tumors, and renal sarcomas, are rare. Nephroblastoma (Wilms' tumor) is common in children (5 to 6 percent of primary renal tumors). (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma" and "Malignancies of the renal pelvis and ureter".)
An overview of the approach to treatment is presented here; more detailed discussions of specific aspects of treatment are discussed in other topics, as noted below.
GENERAL APPROACH — The initial approach to a patient with presumed renal cell carcinoma (RCC) needs to consider the extent of disease, as well as the patient's age and comorbidity (algorithm 1).
RCC can be classified as:
●Advanced disease – This includes tumor invading beyond Gerota’s fascia or extending into the ipsilateral adrenal gland (T4) and metastatic disease (M1). Either of these findings constitutes stage IV RCC. (See 'Advanced RCC' below.)
An overview of the approach to treatment is presented here; more detailed discussions of specific aspects of treatment are discussed in other topics, as noted below.
LOCALIZED RCC — When patients with renal cell carcinoma (RCC) present with localized disease, definitive therapy can often be curative.
Definitive treatment — Surgery is curative in the majority of patients with RCC who do not have metastases. Surgery is therefore the preferred treatment for patients with stages I, II, and III disease.
Treatment may require a radical nephrectomy, although a partial nephrectomy to preserve renal parenchyma is preferred for appropriately selected patients. The choice of surgical procedure depends upon the extent of disease, as well as patient-specific factors such as age and comorbidity. Surgery may be carried out through a conventional approach or by a minimally-invasive approach such as laparoscopy. (See "Definitive surgical management of renal cell carcinoma".)
In carefully selected patients who present with a resectable primary tumor and a concurrent single metastasis, surgical resection of the metastasis, in conjunction with radical nephrectomy, may be curative. (See "Role of surgery in patients with metastatic renal cell carcinoma".)
Other ablative procedures (eg, cryotherapy, radiofrequency ablation [RFA]) may be an important alternative for patients with relatively small renal masses who are not surgical candidates. (See "Diagnostic approach, differential diagnosis, and treatment of a small renal mass".)
Multiple primary RCCs — Bilateral RCCs are more common among patients with inherited conditions (eg, von Hippel-Lindau disease, tuberous sclerosis, papillary RCC) and occasionally are seen in those with sporadic tumors. In these situations, we recommend surgery. Proper management should include sparing as much renal parenchyma as possible during the initial therapy and monitoring for the development of additional RCCs. (See "Hereditary kidney cancer syndromes" and "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
Active surveillance — Elderly patients and those with significant comorbidity may not be candidates for surgical resection . Although nonsurgical procedures (eg, cryoablation, RFA) may be useful, most small tumors grow slowly and do not become symptomatic or metastasize [2-6]. In addition, up to 40 percent of tumors smaller than 1 cm in size may be benign . In this setting, observation with periodic reevaluation is a reasonable option. (See "Definitive surgical management of renal cell carcinoma", section on 'Active surveillance' and "Diagnostic approach, differential diagnosis, and treatment of a small renal mass".)
Adjuvant therapy — There is no established role for any type of systemic adjuvant therapy after a complete surgical resection, and the use of adjuvant systemic therapy should be limited to formal clinical trials.
Immunotherapy — The ability of immunotherapy to induce objective tumor responses in some patients with advanced RCCs led to the evaluation of interferon-alfa, interleukin-2, and autologous tumor vaccines as adjuvant therapy following surgical resection. However, multiple randomized trials have not demonstrated a survival benefit from any of these approaches. There are no data on checkpoint inhibitor immunotherapy following resection of high-risk RCC, although phase III studies with T cell checkpoint inhibitors are being planned. (See "Immunotherapy of renal cell carcinoma", section on 'Adjuvant immunotherapy'.)
Anti-angiogenic and targeted therapy — Adjuvant therapy with agents targeting the vascular endothelial growth factor (VEGF) pathway has not demonstrated any improvement in overall survival in the adjuvant setting, although these agents can prolong overall survival in patients with metastatic clear cell RCC. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'VEGF TKIs'.)
Two large randomized trials have reported results:
●In the ASSURE trial, 1943 patients with completely resected intermediate-, high-, or very high-risk RCC were randomly assigned to sunitinib, sorafenib, or placebo for up to one year . The primary endpoint of the trial was disease-free survival (DFS).
•There was no improvement in DFS (median 5.8, 6.1, and 6.6 years for sunitinib, sorafenib, and placebo, respectively. For sunitinib versus placebo, hazard ratio [HR] 1.02, 97.5% CI 0.85-1.23; for sorafenib versus placebo, HR 0.97, 97.5% CI 0.80-1.17). There was also no significant difference in overall survival for any of the three treatment arms (for sunitinib versus placebo, HR 1.17, 97.5% CI 0.90-1.52; for sorafenib versus placebo, HR 0.98, 97.5% CI 0.75-1.28).
•Grade 3 or greater toxicity was significantly increased with both sunitinib and sorafenib compared with placebo (hypertension 17 and 16 versus 4 percent, hand-foot syndrome 15 and 33 versus 1 percent, rash 2 and 15 versus <1 percent, and fatigue 18 and 7 versus 3 percent).
●In the S-TRAC trial, 615 patients with high-risk clear cell RCC were randomly assigned to sunitinib (50 mg/day for four weeks out of each six-week cycle) or to placebo . At a median follow-up of 5.4 years, DFS, the primary endpoint of the trial, was significantly increased in those receiving sunitinib (median 6.8 versus 5.6 years, 59.3 versus 51.3 percent disease free at five years, HR 0.76, 95% CI 0.59-0.95). At the time of data cutoff, data were not mature enough to evaluate overall survival, a secondary endpoint of the trial, although the number of deaths in the two treatment arms was equal. Toxicity was significantly increased with sunitinib compared with placebo, the most common serious side effects being palmar-plantar erythrodysesthesia and hypertension.
Another large phase III trial using girentuximab (an antibody targeting carbonic anhydrase IX) failed to demonstrate any benefit in either DFS or overall survival . The six-year median DFS endpoints of this trial and the ASSURE and S-TRAC trials [8,9] highlight the difficulty of conducting adjuvant trials in patients with high-risk resected RCC in an efficient manner.
Randomized clinical trials are ongoing with two other VEGF receptor inhibitors, pazopanib (NCT01235962) and axitinib (NCT01599754), and the mechanistic (mammalian) target of rapamycin (mTOR) inhibitor, everolimus (NCT01120249).
Surveillance after resection — Careful surveillance following surgical resection is important to permit early diagnosis of relapse when the tumor burden is limited. The response to therapy of patients who relapse is best in patients with a good performance status and a limited tumor burden. Furthermore, some patients who have a solitary recurrence may be cured with surgical metastasectomy. (See "Surveillance for metastatic disease after definitive treatment for renal cell carcinoma".)
ADVANCED RCC — Many renal cell carcinomas (RCCs) are clinically silent for much of their natural history. Thus, the diagnosis is frequently not made until disease is locally advanced (and unresectable) or has metastasized. In addition, many patients who initially are resectable eventually recur. Systemic therapy (immunotherapy, molecularly targeted agents), surgery, and radiation all may have a role depending upon the extent of disease, sites of involvement, and patient-specific factors.
In general, systemic therapy is initiated promptly when unresectable disease, either metastatic or locally advanced disease, is present. However, for asymptomatic patients with a limited disease burden and no poor prognostic features, close active surveillance may represent an alternative for those wanting to defer the initiation of therapy and its attendant toxicity until more compelling disease progression is documented .
Systemic therapy of clear cell RCC — Immunotherapy (high-dose interleukin-2 [IL-2], nivolumab) and molecularly targeted therapy are the primary systemic modalities for the management of patients whose disease is not controlled by definitive locoregional therapy (table 2 and algorithm 2).
•Immunotherapy with high-dose IL-2 is preferred for the initial therapy of advanced clear cell renal cell carcinoma. However, the use of high-dose IL-2 requires access to a center capable of managing the toxicity associated with this treatment regimen and should be limited to patients with a good Karnofsky performance status (KPS; ≥80 percent) (table 3) and intact organ function. IL-2 can induce durable long-term remissions in approximately 10 percent of patients. (See 'Immunotherapy' below and 'Molecularly targeted therapy' below.)
•For patients who are not candidates for high-dose IL-2, anti-angiogenic targeted immunotherapy or participation in a protocol involving a PD1 or PDL1 pathway blocker are the primary options. Among the available agents, preferred options for initial therapy include pazopanib and sunitinib. (See 'Molecularly targeted therapy' below.)
•For patients who progress after initial immunotherapy (eg, IL-2 or protocol therapy) we suggest treatment with the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) axitinib rather than sorafenib. For patients without access to axitinib or sorafenib, there are a number of alternative agents that can be administered, including bevacizumab, pazopanib, and sunitinib. (See 'Anti-angiogenic (VEGF pathway)' below and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma".)
•For patients who have progressed after initial treatment with a VEGF pathway inhibitor and who have not received prior immunotherapy, treatment with nivolumab is preferred; cabozantinib is an alternative. Both nivolumab and cabozantinib are superior to the mechanistic target of rapamycin (mTOR) inhibitor everolimus; although these agents have not been directly compared, nivolumab appears to be associated with less toxicity. (See "Immunotherapy of renal cell carcinoma", section on 'Nivolumab and checkpoint inhibition' and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Cabozantinib'.)
●Subsequent therapy – Patients who have progressed following one or two courses of anti-angiogenic therapy and immunotherapy may benefit from treatment with an alternative targeted agent. Patients should be encouraged to participate in formal clinical trials whenever possible.
Immunotherapy — Immunotherapy is an important option for the management of patients with advanced clear cell RCC, both as initial therapy (high-dose IL-2) or as secondary therapy after molecularly targeted therapy (nivolumab). (See "Immunotherapy of renal cell carcinoma" and "Principles of cancer immunotherapy".)
Interleukin-2 — Immunotherapy with high-dose bolus IL-2 can activate an immune response against RCC that results in tumor regression in a minority of patients. Although treatment is associated with severe toxicity, responses often persist for many years, even in the absence of additional therapy, and the majority of complete responders remain free of relapse long-term. High-dose IL-2 is an important option for carefully selected patients who are able to tolerate the toxicity associated with this approach and who have access to this treatment. (See "Immunotherapy of renal cell carcinoma", section on 'Interleukin-2'.)
Nivolumab — Nivolumab is an anti-PD-1 antibody that was initially developed for patients with advanced melanoma and non-small cell lung cancer. Initial studies in advanced clear cell RCC showed significant activity in patients who had progressed on or after targeted therapy. In a large phase III trial, nivolumab prolonged overall survival compared with everolimus as second-line therapy in patients progressing after initial treatment with a VEGF TKI, and nivolumab is the preferred option in this setting . Nivolumab was approved by the US Food and Drug Administration (FDA) for patients with advanced renal cell carcinoma whose disease has progressed following antiangiogenic therapy, based upon this trial . (See "Immunotherapy of renal cell carcinoma", section on 'Efficacy of nivolumab'.)
Interferon-alfa — The use of IFNa has largely been replaced by molecularly targeted agents and immunotherapy with high-dose IL-2 or nivolumab. In older trials using a variety of preparations, doses, and schedules, the overall response rate was as high as 15 percent, but most responses were partial and rarely persisted beyond one year. (See "Immunotherapy of renal cell carcinoma", section on 'Interferon-alfa'.)
Molecularly targeted therapy — An understanding of the pathogenesis of RCC at the molecular level has identified the VEGF pathway and mTOR as important targets for therapeutic intervention. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Molecular pathogenesis'.)
Anti-angiogenic (VEGF pathway) — Two different approaches have clinical activity in blocking the VEGF pathway (figure 1): the use of small-molecule TKIs (sunitinib, pazopanib, cabozantinib, axitinib, sorafenib) to block the intracellular domain of the VEGF receptor, and a monoclonal antibody (bevacizumab) to bind circulating VEGF and prevent its activating the VEGF receptor . (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Inhibitors of the vascular endothelial growth factor (VEGF) pathway'.)
●Randomized clinical trials have demonstrated that VEGF receptor inhibitors prolonged overall survival compared with IFNa for the initial management of advanced RCC and are also active in the treatment of patients with disease progression after cytokine therapy. A randomized clinical trial has also demonstrated that cabozantinib is superior to the mTOR inhibitor everolimus as second-line therapy.
●An alternative approach to interrupting the VEGF pathway uses the anti-VEGF monoclonal antibody, bevacizumab, which has significant activity in combination with IFNa in both untreated patients and those who have failed cytokine therapy.
mTOR inhibitors — The mTOR pathway is downstream of the phosphoinositide 3-kinase and Akt pathway that is regulated by the phosphatase and tensin homolog (PTEN) tumor suppressor gene (figure 1). Inhibition of the mTOR pathway has the potential to inhibit tumor progression at multiple levels. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Inhibitors of the mTOR pathway'.)
However, mTOR inhibitors have a limited role as single agents in advanced RCC. Their principal utility may be in patients whose disease is refractory to initial treatment with VEGF receptor TKIs and/or those patients whose tumors have mutations in the PI3K pathway. Except for this, their use is relegated to fifth- or greater-line therapy in patients whose disease has progressed on multiple VEGF pathway inhibitors, nivolumab, and cabozantinib.
●Temsirolimus – In the four-armed phase II BEST trial of patients who had not received prior targeted therapy, temsirolimus plus either bevacizumab or sorafenib had a worse therapeutic index than either bevacizumab alone or the combination of bevacizumab plus sorafenib . In the INTORSECT trial in patients who had previously been treated with sunitinib, overall survival was significantly worse than with sorafenib . (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Bevacizumab' and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Temsirolimus'.).
●Everolimus – In the RECORD-3 trial, everolimus was inferior to sunitinib as first-line therapy with advanced RCC . In phase III trials in previously treated patients, everolimus was inferior to both nivolumab  and cabozantinib . (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Everolimus'.)
Chemotherapy and hormonal therapy — Both chemotherapy and progestational agents had only very limited activity in early studies prior to the development of immunotherapy and molecularly targeted therapy.
●Chemotherapy does not have an established role in the management of patients with advanced or metastatic RCC . A review of early studies reported that fluorinated pyrimidines were the most active agents, but the objective response rate was only 5 to 10 percent .
Subsequent studies with capecitabine and a formulation of the fluorouracil prodrug tegafur have also shown evidence of at least some activity , as have studies with gemcitabine [22-24]. Phase II studies using combinations of gemcitabine plus capecitabine have reported response rates of 8 to 24 percent [25-29], and at least one study has suggested that this combination may be more effective when given in combination with sorafenib . Additional clinical trials will be required to determine whether this approach might have a role in patients who are no longer responsive to immunotherapy or molecularly targeted agents.
●Progestational agents do not have significant antitumor activity. Medroxyprogesterone is the most widely studied. Despite occasional reports of responses, a review of medroxyprogesterone treatment concluded that RCCs are neither hormone-dependent nor hormone-responsive , although some patients with severe anorexia may derive symptomatic benefit from hormonal therapy. (See "Pharmacologic management of cancer anorexia/cachexia", section on 'Progesterone analogs'.)
There is no evidence that other hormonal agents (eg, androgens, antiestrogens, or combinations of hormones and chemotherapy) are effective [32,33].
Systemic therapy of non-clear cell carcinoma — The activity of molecularly targeted agents (sunitinib, sorafenib, temsirolimus) in patients with non-clear cell RCC has yet to be evaluated in phase III clinical trials. However, a systematic review and meta-analysis of various phase II and retrospective studies found that these agents have limited activity in patients with non-clear cell RCC, with response rates significantly lower than in clear cell RCC . In addition, treatment with an inhibitor of the MET oncogene may have activity, specifically in papillary RCC . Patients with non-clear cell RCC do not appear to respond to cytokine-based immunotherapy [36,37]. A case report described a dramatic response to nivolumab in a patient with papillary RCC with sarcomatoid features , although confirmatory data are needed before such a treatment approach can be endorsed. (See "The treatment approach to non-clear cell renal carcinoma" and "Immunotherapy of renal cell carcinoma", section on 'Interleukin-2'.)
Subsets of patients with non-clear cell tumors occasionally respond to chemotherapy. Major responses have been reported with various combinations of platinum agents, taxanes, gemcitabine, or ifosfamide in patients with collecting duct tumors [39-42] and sarcomatoid RCCs [43-45]. Renal medullary carcinoma may also be responsive to platinum-based combination chemotherapy regimens [46,47], anthracyclines , or bortezomib [49,50].
Surgery — Most patients with stage IV RCC have unresectable disease and require systemic therapy. However, surgery has a role in the management of some patients.
Radical nephrectomy — For a subset of patients in whom the only evidence of advanced disease is the direct involvement of the ipsilateral adrenal gland, a radical nephrectomy that includes adrenalectomy is potentially curative. (See "Definitive surgical management of renal cell carcinoma", section on 'Adrenal gland involvement'.)
Cytoreductive nephrectomy — Removal of the primary tumor (cytoreductive or debulking nephrectomy) should be performed in all patients when it is clinically feasible and justifiable (good performance status, 75 percent debulking possible, no symptomatic metastatic disease) before initiating systemic therapy. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Nephrectomy'.)
Randomized clinical trials demonstrated that patients who undergo a cytoreductive nephrectomy prior to IFNa immunotherapy had improved survival compared with those with an intact primary tumor [51,52]. Careful patient selection is critical to avoid surgery in patients who will not be able to subsequently receive immunotherapy.
No prospective clinical trial data are available on the merits of cytoreductive nephrectomy in patients who will be treated with VEGF pathway inhibitors or other types of immunotherapy. However, the general consensus is that cytoreductive nephrectomy is indicated in this setting as well.
Metastasectomy — Surgical resection of a single or limited number of metastases is a reasonable option for carefully selected patients. This occasionally is done in conjunction with a radical nephrectomy, but may also be performed following a relapse after surgery. In addition, surgery is sometimes performed to resect residual disease in patients who have had a major but less than complete response to systemic immunotherapy. (See "Role of surgery in patients with metastatic renal cell carcinoma" and "Immunotherapy of renal cell carcinoma".)
Radiation therapy — Although RCC has been characterized as a radioresistant tumor, conventional and stereotactic radiation therapy (RT) are frequently useful to treat a single or limited number of metastases. In these settings, the utility of RT is similar to that in metastases from other tumor types.
Examples of situations where RT is useful include:
●Painful bone metastases (See "Radiation therapy for the management of painful bone metastases".)
●Brain metastases (See "Overview of the treatment of brain metastases".)
●Painful recurrences in the renal bed
RT has been used as an adjuvant following nephrectomy in patients at high risk for local recurrence [53-55], but its role in this setting remains unproven and is generally discouraged.
SUMMARY AND RECOMMENDATIONS
Localized disease — For patients with a resectable stage I, II, or III renal cell carcinoma (RCC), we recommend surgery as the primary treatment approach (algorithm 1) (Grade 1A). (See "Definitive surgical management of renal cell carcinoma".)
●Radical nephrectomy has been the most widely used approach and remains the preferred procedure when there is evidence of invasion into the adrenal, renal vein, or perinephric fat. (See "Definitive surgical management of renal cell carcinoma", section on 'Radical nephrectomy'.)
●Partial nephrectomy (either open or laparoscopic) is an alternative for smaller tumors and is particularly valuable in patients with bilateral or multiple lesions, those with inherited syndromes in whom there is an increased risk of an additional subsequent primary tumor, and those with impaired renal function. (See "Definitive surgical management of renal cell carcinoma", section on 'Partial nephrectomy'.)
●For elderly patients and those with significant comorbid disease, ablative techniques (cryoablation, radiofrequency ablation) are an alternative. (See "Radiofrequency ablation and cryoablation for renal cell carcinoma".)
●Active surveillance may be an option for patients with small asymptomatic lesions. (See "Definitive surgical management of renal cell carcinoma", section on 'Active surveillance'.)
●Following complete resection of a localized RCC, there is no role for adjuvant therapy with either immunotherapy, vascular endothelial growth factor (VEGF) pathway inhibitors, or mechanistic target of rapamycin (mTOR) inhibitors, except in the context of a formal clinical trial.
Advanced clear cell RCC — The general approach to patients with advanced clear cell RCC is summarized in the table and algorithm (table 2 and algorithm 2 and algorithm 1). (See 'Systemic therapy of clear cell RCC' above.)
●For patients who have a good performance status and intact organ function, we suggest high-dose interleukin-2 (IL-2) rather than anti-angiogenic targeted therapy (Grade 2B). (See 'Immunotherapy' above and "Immunotherapy of renal cell carcinoma", section on 'Interleukin-2' and "Immunotherapy of renal cell carcinoma", section on 'Nivolumab and checkpoint inhibition'.)
●For patients who will be treated with a molecularly targeted agent, we prefer either pazopanib or sunitinib. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Inhibitors of the vascular endothelial growth factor (VEGF) pathway'.)
●For patients who progress after immunotherapy (IL-2), we suggest axitinib rather than sorafenib (Grade 2B). For patients without access to axitinib or sorafenib, there are a number of alternative agents that could be administered, including bevacizumab, pazopanib, and sunitinib. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Axitinib'.)
●For patients who progress after an initial VEGF pathway inhibitor, we recommend treatment with nivolumab, cabozantinib, or the combination of lenvatinib plus everolimus rather than single agent everolimus (Grade 1B). In this setting, we suggest nivolumab rather than antiangiogenic therapy (Grade 2C). There are no direct comparisons between nivolumab and these alternative approaches, and in phase III trials, nivolumab, cabozantinib, and the combination of lenvatinib plus everolimus had a similar impact on overall survival. However, nivolumab has demonstrated a better safety profile. (See "Immunotherapy of renal cell carcinoma", section on 'Nivolumab and checkpoint inhibition' and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Cabozantinib'.)
Axitinib is also an option and preferred over sorafenib, particularly in patients who have shown some benefit from first line vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy. Neither nivolumab nor cabozantinib have been compared with axitinib in clinical trials. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Axitinib'.)
Treatment beyond the second line
●Patients who have progressed following an initial molecularly targeted agent and immunotherapy may benefit from treatment with an alternative targeted agent. These could include axitinib or cabozantinib rather than everolimus or sorafenib. Patients should be encouraged to participate in formal clinical trials whenever possible.
Advanced non-clear cell RCC
●For patients with non-clear cell RCC, we suggest molecularly targeted therapy rather than chemotherapy (Grade 2C). However, some types of non-clear cell RCC are reported to be chemosensitive (including collecting duct, sarcomatoid, and medullary RCC). (See "The treatment approach to non-clear cell renal carcinoma" and 'Systemic therapy of non-clear cell carcinoma' above.)
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