Immunotherapy of renal cell carcinoma | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Immunotherapy of renal cell carcinoma

UpToDate: Immunotherapy of renal cell carcinoma


Surgical resection of localized renal cell cancer (RCC) can be curative for localized disease, but many patients eventually recur. In addition, many RCCs are clinically silent for much of their course, and the initial diagnosis is often delayed until disease is either locally advanced and unresectable or metastatic. The prognosis for patients with advanced or metastatic RCC can vary widely from a few months to many years depending on the clinical, pathologic, laboratory, and radiographic features of disease.

For most patients with advanced RCC, anti-angiogenic therapy or the administration of a molecularly targeted agent are the preferred treatments. However, for select patients, immunotherapy can result in durable long-term remissions. Therefore, immunotherapy continues to be a treatment option for some patients with advanced RCC.

This topic will review immunotherapy of advanced renal cell carcinoma, including the use of IL-2, IFNα, and experimental approaches. An overview of the treatment approach to RCC, prognostic factors in RCC, and the use of anti-angiogenic and molecularly targeted therapy are discussed separately.

Rationale for immunotherapy

Removal of primary RCCs can evoke an immune response that occasionally results in spontaneous and dramatic remissions in metastases, particularly in the lung [1,2]. Various immunotherapeutic strategies have been used to augment antitumor immunity, including the administration of cytokines, specific antitumor immunotherapy, adoptive immunotherapy, the induction of a graft-versus-tumor response via allogeneic hematopoietic stem cell transplantation, and nonspecific stimulators of the immune system.

Clinically useful antitumor activity has been seen with the cytokines interleukin-2 (IL-2) and interferon alfa (IFNα); among the immunotherapies, high-dose IL-2 was established as the preferred treatment for patients with advanced RCC and good organ function in the 1990s [3]. Although the mechanisms of action of IL-2 and IFNα are poorly understood, the induction of antitumor immunity in murine models involved direct killing of tumor cells by activated T cells and natural killer (NK) cells. In addition, IFNα may have antiangiogenic effects.

Choice of therapy

For previously untreated patients with RCC, both immunotherapy and molecularly targeted agents are reasonable options.

  • For patients with a good Karnofsky performance status (KPS) (≥80%) (table 1) and intact organ function, we suggest immunotherapy rather than targeted therapy. Of the available immunotherapeutic treatments, we prefer IL-2 rather than interferon alfa or other immunotherapeutic approaches. IL-2 results in a durable long-term remission in approximately 10% of patients.
  • For patients who are not candidates for or who decline IL-2 (including those patients without access to IL-2 therapy), we recommend molecularly targeted therapy.

Interleukin-2

The initial use of interleukin-2 (IL-2) in RCC combined high-dose bolus therapy with the infusion of lymphokine-activated killer (LAK) cells [4]. Dramatic and durable responses were reported in some patients [5,6]. Subsequent studies found that high-dose bolus IL-2 alone was as active as the combination of IL-2 and LAK [7-9].

High-dose IV bolus

The efficacy of high-dose bolus IL-2 is based upon its ability to induce durable, high-quality remissions in a minority of patients [8,10].

In seven phase II studies, recombinant IL-2 (600,000 to 720,000 international units per kg) was administered as a 15 minute intravenous (IV) infusion every eight hours over five consecutive days (up to 14 consecutive doses). A course of therapy consisted of such two cycles, beginning on days 1 and 15. Responding patients and those with stable disease were retreated approximately every 12 weeks for a maximum of three courses.

High-dose bolus IL-2 treatment was associated with severe toxicity (table 2A-B) [11]. Thus, this protocol was restricted to carefully selected patients with excellent organ function who could be treated in a setting capable of providing blood pressure support.

The following results were reported for 259 patients treated with this high-dose bolus IL-2 schedule at the National Cancer Institute between 1986 and 2006 [8,10]:

  • Objective responses were observed in 53 patients (20%); these included 30 partial responses (PRs) and 23 complete responses (CRs). Maximal response often took a prolonged period to develop, and surgery rendered six patients disease free after an initial PR to IL-2 treatment.
  • Among the patients who achieved a CR, 19 of 23 (83%) remained free of recurrence at last follow-up. The four patients who relapsed all did so within the first four years after treatment. In contrast, all of the patients who had a PR eventually recurred, predominantly within the first three years.

Similar results were seen in another series of 212 patients treated with high-dose IL-2, in which an overall response rate of 20% was observed. This included 16 patients (8%) with complete responses and a median survival of over 10 years [12].

Thus, it appears that many responding patients who were progression-free for more than three years or who underwent posttreatment surgical resection were cured of metastatic RCC.

Alternative schedules

Alternative schedules have been evaluated to increase the antitumor efficacy of IL-2 or decrease its toxicity while maintaining activity. These approaches have included using intermediate or low doses of IL-2 by continuous infusion or subcutaneously (SC) or by combining IL-2 with IFNα.

Results from several large randomized trials have been reported.

  • NCI Trial – The National Cancer Institute (NCI) conducted a large-scale randomized phase III trial comparing the standard high-dose bolus IL-2 schedule with a low-dose intravenous bolus regimen using 10% of the standard dose and with an outpatient regimen using SC IL-2 [13]. The main results were:
    • Among the 306 patients randomly assigned to high-dose or low-dose intravenous IL-2, the response rate was significantly higher with high-dose therapy (21 versus 13% with the low-dose schedule), with a trend toward more durable responses. Although toxicities were also significantly greater in the high-dose group (particularly hypotension), there were no deaths attributable to IL-2 in either arm.
    • Among the 190 patients assigned to high-dose IV IL-2 or SC IL-2, there was a significantly higher response rate with high-dose IV IL-2 (21 versus 10% with the SC schedule).
    • There were no differences in overall survival among the three groups. However, a more appropriate endpoint would have been a landmark survival analysis, since the main benefit of IL-2 administration is not the initial response rate but the induction of durable, complete responses.
    • Cytokine Working Group Trial – The Cytokine Working Group (CWG) evaluated outpatient administration of IL-2 plus IFN (both administered as a subcutaneous injection) in a phase III trial of 193 patients, using high-dose bolus IL-2 as the comparison regimen [14]. The main results were:
    • A significantly higher objective response rate was seen with high-dose bolus IL-2 compared with the outpatient schedule (23 versus 10%).
    • Eight patients treated with high-dose IL-2 achieved a CR and 10 were progression-free at three years. Only three patients had a CR with the outpatient schedule, and none were durable.
    • A trend toward improved survival was noted in the group treated with high-dose IL-2 (17.5 versus 13 months).
    • Patients receiving high-dose IL-2 had a diminished quality of life (QOL) on some symptoms scales early in therapy, but experienced overall improved functional and symptomatic QOL during the course of treatment, compared with those receiving the outpatient combination [15].
  • French multicenter trial – A multicenter French trial randomly assigned 425 patients to intermediate-dose IL-2 administered by continuous IV infusion, subcutaneous IFNα, or a combination of these agents by the same routes of administration [16]. Although the response rate was significantly higher for combined therapy than for either single agent (18.6 versus 6.5 and 7.5%, IL-2 and IFNα, respectively), the differences in survival at one year were not statistically significant.

IL-2 plus cellular therapy

Initial trials comparing high-dose IL-2 plus lymphokine-activated killer (LAK) cells to IL-2 alone concluded that the efficacy of high-dose bolus IL-2 was equivalent to that of IL-2/LAK cells.

The combination of low-dose, continuous infusion IL-2 and CD8-positive tumor infiltrating lymphocytes (TILs) appeared to give an improved response rate in a phase II study [17]. However, in a subsequent trial, 160 patients with advanced renal cell carcinoma were randomly assigned to IL-2 alone or with an infusion of autologous CD8-positive TILs [18]. Intention to treat analysis revealed low response rates for both treatment arms and no survival difference. Unfortunately, many patients assigned to the TILs arm did not receive TILs due to technical problems. Although this study is difficult to interpret, there does not appear to be a clear benefit from the addition of TILs to low-dose IL-2.

Predictors of response

Responses to high-dose IL-2 are often of long duration and high quality, which must be balanced against the cost, limited access, and toxicity associated with high-dose IL-2 treatment. Thus, efforts have been made to identify clinical, histologic, and molecular characteristics that can identify the patient subsets that are most likely to benefit from this approach.

Clinical factors: Clinical factors that reflect a large tumor burden or rapid disease progression are associated with less frequent responses that are of shorter duration. These factors include the presence of more than one site of metastatic disease, a progression-free interval of less than one year, and the presence of liver or mediastinal lymph node involvement [16]. Patients with all of these characteristics had >70% chance of rapid disease progression and a median survival of six months in one series.

Prior nephrectomy and time from nephrectomy to relapse are important predictors of improved survival in patients receiving IL-2 therapy. In one report, patients who began immunotherapy at least six months after nephrectomy had the best median survival and a 46% three-year survival rate [19].

Other factors associated with a favorable prognosis include a good performance status and the absence of bone metastases [20]. Clinical or laboratory observations after the initial treatment that correlate with a subsequent antitumor response and an improved prognosis include the development of thrombocytopenia [21], thyroid dysfunction [22], rebound lymphocytosis [23], low circulating levels of monocytes and granulocytes [24], and elevation of tumor necrosis factor (TNF) and interleukin-1 (IL-1) [25].

Histology and CAIX expression: Responses to immunotherapy are typically observed in patients with clear cell RCCs. This was illustrated in a report in which pathology specimens were obtained from 231 patients undergoing IL-2 therapy [26]. The primary tumor was available for analysis in 163 cases. Responses were observed in 30 of 146 patients with clear cell carcinoma (21%), compared with 1 of 17 cases with nonclear cell histology (6%). Similarly, in the prospective, single-arm SELECT trial, 120 patients were treated with high-dose IL-2 [27]. In preliminary results presented at the 2010 American Society of Clinical Oncology (ASCO) meeting, objective responses were seen in 34 of 115 patients (30%) with clear cell histology but 0 of 5 with nonclear cell histology. As a consequence, many oncologists do not use IL-2 therapy in patients with nonclear cell histology.

Among the patients with clear cell carcinomas, other histologic features may provide additional prognostic information. In a retrospective series, responses to IL-2 were associated with the presence of alveolar features in more than 50% of the sample, and an absence of papillary features or granular features [26]. Similarly, high levels of carbonic anhydrase IX (CAIX) expression appear to be associated with a more favorable prognosis and potentially a greater likelihood of a response to immunotherapy [28,29]. Although retrospective studies suggested that these parameters might have utility in predicting responsiveness to IL-2 therapy, efforts to combine histologic features and CAIX expression to predict responsiveness to IL-2 were unsuccessful in the prospective SELECT trial [27].

Sarcomatoid RCC: Sarcomatoid features or sarcomatoid dedifferentiation can be seen in all types of RCC specimens. The role of immunotherapy in patients with the sarcomatoid variant of RCC is unclear. One review of 31 consecutive cases of sarcomatoid RCC found that those treated with nephrectomy followed by high-dose IL-2 had a median survival of more than ten months, which was significantly longer than that of patients undergoing surgery alone or any other form of immunotherapy [30]. Other series report an objective response in 25 to 33% of patients receiving systemic immunotherapy [31]. Nonetheless, it is generally believed that durable responses to immunotherapy are unlikely in patients with tumors containing sarcomatoid features.

Patients with tumors showing predominantly sarcomatoid features also have been reported to respond to doxorubicin-based chemotherapy [32,33], as well as molecularly targeted therapies [34,35], so such approaches can be considered alternatives in this patient population, especially in patients with non-clear cell tumors. (See «Overview of the treatment of renal cell carcinoma», section on ‘Chemotherapy’.)

Toxicity — Treatment with IL-2 is associated with severe toxicity affecting multiple organ systems. These complications include hypotension, cardiac arrhythmias, metabolic acidosis, fever, nausea and vomiting, dyspnea, edema, oliguria and renal failure, neurotoxicity, and dermatologic complications. Use of high-dose regiments requires treatment in a setting where blood pressure support can be provided. Guidelines are available for the clinical management of these complications (table 2A-B) [36].

The mechanisms underlying IL-2 toxicity are not fully understood. Several mechanisms have been proposed:

  • IL-2 is a strong stimulator of proinflammatory cytokines (eg, IL-1, TNFa, and interferon gamma [IFNg]) [37-39] and of nitric oxide [40]. These substances may mediate much of the treatment-related toxicity.
  • A protein fragment of the IL-2 molecule that has tentatively been identified may be responsible for vasopermeability [41].
  • In a series of 18 patients, serum levels of angiopoietin 2 rose progressively in all cases with high-dose IL-2 therapy [42]. Elevated levels of serum angiopoietin 2 have previously been identified in septic patients with vascular leak syndrome.

In contrast, the antitumor response is thought to be mediated via cellular immune mechanisms, raising the possibility of dissociating toxicity from antitumor efficacy by combining cytokine inhibitors with IL-2.

Several experimental approaches have been tried in an effort to separate the toxicity of IL-2 from its antitumor activity, but these approaches have not proven useful in a clinical setting [43-50].

Relapses after response

Most patients with metastatic RCC who achieve a PR with IL-2 eventually relapse. In a series from the NCI, for example, 86% of 64 patients who had a PR relapsed, as opposed to less than half of the 43 who had a CR [51]. Relapses primarily occurred in new sites in those with a CR, and in new or old sites in those with a PR. In patients with isolated recurrences, surgical metastasectomy has occasionally been successful.

Patients who relapsed after an initial response had a low rate of response (2%) to retreatment with IL-2 [51]. Given these low response rates, further IL-2 therapy is generally not indicated. Such patients should be considered for antiangiogenic therapy with agents like sorafenib or sunitinib or for participation in clinical trials.

Interferon α

Monotherapy

The activity of monotherapy with IFNα in metastatic RCC has been extensively evaluated in several large, well-designed trials [16,52-55]. Using a variety of preparations, doses, and schedules, the overall response rate may be as high as 15%; the median time to response is about four months, and most responses are partial and rarely persist beyond one year. Although no clear dose-response relationship has been shown, daily doses ranging from 5 to 10 MU appear to have the most favorable therapeutic index.

The impact of IFNα on survival was demonstrated in a Cochrane meta-analysis that included four studies involving a total of 644 patients [56]. Treatment with IFNα was superior to controls (odds ratio for death at one year 0.56, 95% CI 0.40-0.77 and an overall hazard ratio for death 0.74, 95% CI 0.63-0.88). The weighted average median improvement in survival was 3.8 months.

IFNα combinations

The general availability and manageable toxicity of IFNα made it an attractive agent to combine with novel treatments and to use as the control in phase III trials. With the advent of active antiangiogenic and molecularly targeted agents, the role for IFNα in the treatment of patients with advanced RCC has diminished considerably.

IFNα plus IL-2 — Combinations of IFNα plus IL-2 were studied in patients with RCC, both with and without cytotoxic agents, based upon promising results in murine tumor models [57,58]. IFNα upregulates the expression of HLA class I and tumor-associated antigens, thereby potentially increasing the immunogenicity of tumor cells and their susceptibility to IL-2-mediated cell lysis.

These combinations have various schedules and routes of administration for IL-2. These variations have included:

  • IL-2 as a high-dose IV bolus injection [20,59-63].
  • Intermediate-dose levels of IL-2, administered as a continuous IV infusion [14,16].
  • IL-2 as a low-dose SC injection, often including the addition of various cytotoxic agents [64-71].

Some phase II studies have reported either a higher response rate or lower toxicity than would have been expected with high-dose IL-2. However, large randomized trials with these combinations have been disappointing. These approaches have not demonstrated an improvement in overall survival compared with IFNα alone or a comparable level of durable long-term remissions compared with high-dose IL-2 [72].

IFNα plus bevacizumab — For patients with metastatic RCC, the administration of IFNα plus bevacizumab is an approved and active regimen. However, to what extent IFNα contributes to the efficacy of the combination is unclear as a head to head comparison against bevacizumab alone has not been studied. The data to support the administration of IFNα plus bevacizumab are discussed separately.

Chemotherapy — Although phase II studies suggested increased activity when IFNα was combined with chemotherapy, randomized trials have not demonstrated increased survival when combination regimens were compared with IFNα monotherapy [73,74] or from the addition of cis-retinoic acid to IFNα [67,75,76].

The most promising results were seen with the combination of 5-fluorouracil and IFNα, which has produced responses in nearly one-third of patients in some trials [77-79], including occasional patients who have progressed following IL-2 therapy [80]. However, randomized trials have not compared this regimen with IFNα alone.

Prognostic factors

Outcome and prognostic factors were analyzed in a retrospective review of 463 patients treated at Memorial Sloan Kettering Cancer Center with advanced RCC following treatment with IFNα in six prospective clinical trials [55]. Key findings included the following:

  • The median survival and time to progression (TTP) were 13 and 4.7 months, respectively. The proportion of patients remaining progression-free at 6, 12, 24, and 36 months was 42, 24, 14, and 8%, respectively.
  • Five factors independently predicted for poorer survival: KPS <80% (table 1), serum lactic dehydrogenase (LDH) >1.5 times the upper limit of normal, corrected serum calcium >10 mg/dL (2.5 mmol/L), serum hemoglobin below the lower limit of normal, and an interval of less than 12 months from the initial diagnosis to use of IFNα.
  • Prognosis differed significantly for those with none (good risk), one or two (intermediate risk), or three or more of the Memorial Sloan Kettering Cancer Center risk factors (poor risk) (table 3). The good risk patients had better median survival (30 versus 14 and 5 months for intermediate and poor risk patients), survival at one year (83 versus 58 and 20%), two years (55 versus 31 and 6%), and three years (45 versus 17 and 2%).

IFNα versus molecularly targeted therapy

The development of agents targeting vascular endothelial growth factor (VEGF), VEGF receptors, and the mammalian target of rapamycin (mTOR) has provided agents that are both more active and potentially less toxic than IFNα. Both sunitinib, a VEGF receptor inhibitor, and temsirolimus, an mTOR inhibitor, have shown significant clinical activity with prolonged progression-free or overall survival or both compared with IFNα in randomized clinical trials. On the other hand, no benefit was seen in terms of median PFS for sorafenib relative to IFNα in a randomized phase II trial conducted in patients with previously untreated RCC. The results of these trials are discussed separately. (See «Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma».)

Cytoreductive (debulking) nephrectomy

Patients presenting with metastatic RCC generally have a poor prognosis. However, there are case reports of regression of metastases after removal of the primary tumor (cytoreductive or debulking nephrectomy), although this is seen in 1% of patients or less [81]. More importantly, two randomized trials demonstrated a survival benefit following removal of the primary tumor in carefully selected patients with metastatic RCC who subsequently underwent immunotherapy with interferon alfa (IFNα) [53,82]. A survival benefit has not been established for cytoreductive nephrectomy in patients with non-clear cell tumors [83].

The results of these trials and the criteria for patient selection are discussed separately. (See «Role of surgery in patients with metastatic renal cell carcinoma», section on ‘Nephrectomy’.)

Other immunotherapy approaches

Anti-PD1 checkpoint inhibition

Immunotherapy with monoclonal antibodies directed against the programmed death 1 (PD-1) protein has become an important advance in the management of advanced melanoma. These agents are now being evaluated for their efficacy in a variety of other malignancies.

  • The original dose escalation study included 34 patients with advanced, previously treated renal cell carcinoma (RCC), who were treated with either 1 or 10 mg/kg every two weeks for up to 96 weeks [84]. Objective responses were observed in 10 patients (29%) and 9 patients (27%) had stable disease for >24 weeks, and there was no difference in the response rate with the two doses. Five patients stopped treatment while responding, and three of these continued to respond for greater than 45 weeks. The overall survival rates at one, two, and three years were 71, 48, and 44%, respectively.
  • In a phase II trial, 168 patients with metastatic clear cell RCC were randomly assigned to one of three doses of nivolumab (0.3, 2, or 10 mg/kg, given every three weeks) [85]. All patients had previously received at least one agent targeting the vascular endothelial growth factor (VEGF) pathway. No dose-response relationship was observed: the objective response rates at all three doses ranged from 20 to 22%, and the median overall survival was 18, 26, and 25 months for the three dose groups, with a minimum follow-up of 24 months. An international multicenter phase III trial (NCT01668784), in which patients previously treated with VEGFR tyrosine-kinase inhibitors are randomly assigned to either nivolumab monotherapy or everolimus, has completed enrollment. Results are pending.
  • In a phase I study, patients with metastatic RCC were treated with a combination of nivolumab plus ipilimumab in two dosing cohorts [86]. Patients were given maintenance therapy with nivolumab every two weeks. Objective responses were observed in 20 of 44 patients (45%). The median duration of response was 31 weeks in one of the two treatment arms and had not been reached in the other cohort. The 24-week progression-free survival was approximately 65%. An international multicenter phase III trial has been initiated, in which previously untreated patients with metastatic RCC are being randomly assigned to the combination of nivolumab plus ipilimumab or to sunitinib (NCT02231749).

A monoclonal antibody is also being developed that targets the PD-1 ligand. In a phase I study, 55 patients with metastatic RCC were treated with the MPDL3280A antibody [87]. Among the 47 patients evaluable for efficacy, the partial response and stable disease rates were 13 and 32%, respectively; the 24-week progression-free survival rate was 57%. A phase II trial (NCT01984242) is randomly assigning 300 previously untreated patients with locally advanced or metastatic RCC to one of three arms: MPDL3280A plus bevacizumab, MPDL3280A alone, or sunitinib with crossover from the single-agent arms to the combination arm permitted at time of progression.

Dendritic cell vaccines

The effectiveness of vaccination with hybrid cells consisting of fused autologous tumor and allogeneic dendritic cells was assessed in 17 patients with metastatic disease [88]. At a mean follow-up of 13 months, complete tumor regression was observed in four patients and partial regression in two patients. In another phase I/II clinical study using a similarly vaccine, one partial response and three patients with stable disease were observed among nine patients evaluable for response [89].

Similar results were noted using autologous dendritic cells pulsed with lysate made from cultured autologous/allogeneic tumor cells, with peptides that bind to HLA-A2 [90,91].

Additional investigations with dendritic cell vaccines are ongoing, particularly in conjunction with cytokines such as IL-12 or GM-CSF, which are used as vaccine adjuvants to improve the immune response [92].

Other interleukins

Other interleukins that have been evaluated include IL-4 [93], IL-6 [94], and IL-12 [95,96]. The encouraging results seen in animal studies with the combination of IL-12 plus IL-2 [97] have not been confirmed in human clinical trials [98].

Adjuvant immunotherapy

Cytokines

There is no evidence to support a benefit for adjuvant immunotherapy in high-risk patients who have undergone potentially curative surgery. At least seven randomized multicenter trials failed to demonstrate a survival benefit from this approach [99-105].

These include:

  • A trial conducted by the Eastern Cooperative Oncology Group (ECOG) in which 283 patients with stage T3b, T3c, T4 and/or N1 to N3 (table 4) disease were randomly assigned to IFNα therapy or observation [99]. At a median follow-up of 10 years, adjuvant IFNα was not associated with a significant improvement in either disease-free or overall survival.
  • An EORTC trial that randomly assigned 270 patients with Robson stage II or III RCC to IFNα-2a versus no therapy [100].
  • An Italian trial in which 310 patients were randomly assigned immunotherapy with low-dose IL-2 plus IFNα versus no therapy [101].
  • An Italian trial in which 247 patients with Robson stage II or III RCC randomly assigned to IFNα-2b or observation [102].
  • A German trial that randomly assigned 203 patients with resected stage III disease or a completely resected local recurrence or solitary metastasis to IFNα plus 5-FU, eight weeks of low-dose SC IL-2, or no treatment [103].
  • A Cytokine Working Group trial in which 69 high-risk patients were randomly assigned to a single cycle of high-dose IL-2 or observation [104].
  • An EORTC trial that randomly assigned 309 patients to treatment with IL-2, IFNα, plus 5-fluorouracil or to observation [105].

Autologous tumor vaccines

Autologous tumor cell vaccines have been used as an adjuvant in high-risk patients. At least two different vaccines were assessed in randomized phase III clinical trials:

  • A German trial randomly assigned 558 patients with resected pT2-3b, pN0-3, M0 RCC (table 4) to six monthly injections of autologous tumor cell vaccine or no adjuvant therapy [106]. At a minimum 4.5-year follow-up, vaccine therapy was associated with significantly better five-year progression free survival (77 versus 68%). In subgroup analysis, benefit was seen in patients with T3 tumors (five-year PFS 68 versus 50%), but not T2 tumors (five-year PFS 81 versus 75%). Methodologic issues complicate interpretation of these results. Of the 553 patients, 174 were not treated after randomization (99 of the vaccine group and 75 controls) due to ineligibility or inability to produce vaccine.
  • An alternative approach has used peptides from individual tumors in conjunction with heat shock proteins to generate a vaccine. This was used as an adjuvant in a randomized phase III trial that included 728 patients [107]. After a median follow-up of 1.9 years, there was no significant difference in the recurrence rate (38 versus 40%, HR 0.92).

Summary and recommendations

  • For patients with a good Karnofsky performance status (KPS) (≥80%) (table 1) and intact organ function, we suggest high-dose interleukin-2 (IL-2) therapy rather than targeted therapy (Grade 2B).
  • For patients who decline or are not candidates for IL-2 (including those patients without access to IL-2 therapy), we recommend molecularly targeted therapy (Grade 1A).
  • The patients most likely to benefit from IL-2 treatment are those with clear cell carcinomas. Among patients with clear cell RCC, tumors with alveolar features but without papillary or greater than 50% granular features are more likely to respond. Expression of CAIX in more than 85% of cells in a biopsy specimen is also a potential marker for response.
  • For patients with metastatic disease at presentation who are candidates for immunotherapy, we suggest debulking nephrectomy prior to treatment (Grade 2B).
  • We do not administer immunotherapy for patients with metastatic or advanced RCC.

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