NCCN guidelines are one of the most widely used and authoritative clinical practice guidelines in oncology based on evidence-based medicine. The field of kidney cancer diagnosis and treatment has progressed rapidly in recent years, and new versions of NCCN kidney cancer clinical practice guidelines have been continuously released to keep up with the latest cutting-edge advances. This article interprets the latest 2011 2nd edition of NCCN kidney cancer guidelines, hoping to help clinicians understand and apply the guidelines to guide the diagnosis and treatment of kidney cancer.
I. Diagnostic process, staging and prognostic factors of kidney cancer
According to the standard diagnosis and treatment process recommended by the guidelines, medical history, physical examination, laboratory tests, abdominopelvic CT/MRI and chest CT examination are performed for suspicious kidney masses to establish the initial clinical staging diagnosis. For patients with clinical indications, brain MRI or bone ECT imaging is considered to further clarify the diagnosis. Fine needle aspiration biopsy may be considered for patients for whom obtaining the histologic type allows a decision on the next step of surgery or other treatment strategies.
Laboratory tests should include routine blood work, biochemistry (including serum calcium, liver function, blood creatinine, LDH), and urine routine. In particular, hemoglobin, serum calcium and LDH are important indicators for prognosis. the NCCN guidelines define poor prognostic factors for patients with renal cell carcinoma, including the following six indicators: LDH higher than 1.5 times the upper limit of normal, hemoglobin lower than the lower limit of normal, corrected serum calcium level higher than 10 mg/dL, time interval between diagnosis and initiation of systemic therapy less than 1 year, KPS score ≤70, and the number of metastatic organs ≥2; patients with 3 or more of these factors at the same time are considered high-risk patients with poor prognosis.
One of the major updates of this new guideline is that the latest AJCC kidney cancer staging in 2010 has been adopted for disease staging, which will not be discussed here.
Surgical treatment of kidney cancer
Surgery is still the main means of kidney cancer treatment. The surgical treatment recommendations in the new guideline are further refined compared with the old one, and recommendations are provided for all stages of surgery from stage I to III.
Further refinement of surgical treatment recommendations
For patients with clinical diagnosis of stage IA, the guidelines recommend kidney unit preservation surgery; NSS can be performed robotically assisted or laparoscopically in units with conditions (the guidelines also suggest that direct comparative data on open surgery or laparoscopic surgery are not yet available).
Radical nephrectomy should be considered for patients whose tumors are located in the middle of the kidney, for example, where NSS cannot be performed. Some patients with limited renal tumors may be considered for close observation and deferred surgery; studies have shown that close follow-up and surgery when the tumor progresses is a reasonable treatment strategy for small renal tumors; in addition, close observation should be preferred for patients with limited renal tumors who have a short survival expectancy or who have multiple comorbidities that make surgery more risky. The guidelines also recommend thermal ablation for stage IA patients, primarily because it is less invasive and has a similar distant recurrence-free survival as conventional surgery.
Either NSS or RN is the standard treatment recommendation for stage IB patients. For patients with inferior vena cava or intra-atrial thrombus, radical nephrectomy requires cardiac surgeons or cardiopulmonary support due to the involvement of thrombus removal and is therefore recommended to be performed in a qualified and experienced unit.
Some stage IV patients may still benefit from the procedure. For example, patients with resectable primary renal tumors combined with isolated metastases at the time of initial diagnosis, and patients with isolated recurrences or metastases after radical nephrectomy are candidates for surgical resection of both primary and metastatic foci. Primary resection and metastasis resection can be performed simultaneously or electively separately. For patients with resectable primary foci with multiple metastases, guidelines continue to recommend cytoreductive nephrectomy prior to systemic systemic therapy. Patient selection for cytoreductive surgery is important, and the guidelines suggest that patients with only pulmonary metastases, a good prognosis, and a good PS score are most likely to benefit from it. In contrast, palliative nephrectomy is also recommended for metastatic patients with hematuria or other symptoms due to the primary lesion, if surgery is possible.
New general surgical principles
The new version of the guidelines adds more new content to the general surgical principles section. Among the updated indications for NSS are: small unilateral renal tumors, or patients who need to preserve renal function such as isolated kidney, with renal insufficiency, bilateral renal tumors, or familially inherited renal cell carcinoma such as VHL syndrome, while noting that NSS must also be performed by an experienced surgeon.
The new version of the guidelines provides a warning about thermal ablation therapy, noting that it carries a higher risk of local recurrence than surgery, and therefore treatment candidates should be chosen carefully. The guidelines add new indications for cytoreductive nephrectomy, including a PS score of <2 and no brain metastases. The old guideline only suggested that regional lymph node dissection was an option, but the new version adds an explanation by suggesting that lymph node dissection is recommended when lymph node metastasis is suspected on preoperative imaging or found intraoperatively. As for whether to remove the adrenal gland, the new version of the guideline still maintains the view of the original version that adrenalectomy is not required when the adrenal gland is not invaded or judged to be non-high risk of adrenal metastasis.
III. Postoperative adjuvant therapy for kidney cancer
Several randomized studies have shown that postoperative adjuvant therapy with cytokines (IL-2, IFN-α) did not result in prolonged recurrence-free survival (RFS) and overall survival (OS). Recent studies are exploring the value of targeted agents for postoperative adjuvant therapy in renal cancer. To date, however, the status of adjuvant therapy remains uncertain for post-nephrectomy patients including those who have achieved tumor-free status after complete resection of the primary site and isolated metastases, and observation remains the standard postoperative option for these patients.
IV. First-line treatment of metastatic or unresectable clear cell-dominant renal cell carcinoma
The objective remission rates (ORR) reported for IL-2 as well as IFN-α for metastatic clear cell predominant renal cell carcinoma range from 5% to 27%. The clinical benefit of these cytokine treatments is limited, along with a high level of toxicity. However, high-dose IL-2 therapy among them has achieved long-term maintenance of complete remission (CR) or partial remission (PR) in a small proportion of RCC patients, while IFN-α has achieved very few sustained CRs. Therefore the NCCN panel still recommends high-dose IL-2 as a first-line treatment option for metastatic ccRCC, but the new version of the guideline adds an explanation for selective patients treated with high-dose IL-2, i.e., patients with good PS scores and normal organ function.
A large (750 patients) multicenter clinical trial of sunitinib versus IFN-α in first-line treatment of metastatic renal cell carcinoma (mRCC) (Motzer et al.) confirmed that sunitinib had a longer disease-free progression time (PFS) than IFN-α, 11 months and 5 months in the two groups, respectively. ORR was 31% (sunitinib group) and 6% (IFN-α group), respectively. OS was also better in the sunitinib group than in the IFN-α group, at 26.4 months and 21.8 months, respectively.
The AVOREN and CALGB90206 studies established the status of bevacizumab + IFN-α as first-line treatment for mRCC. The two studies enrolled 649 and 732 patients with mRCC, respectively, and resulted in a PFS of 10.2 months vs. 5.4 months and 8.5 months vs. 5.2 months for bevacizumab + IFN-α vs. IFN-α alone, with ORRs of 30.6% vs. 12.4% and 25.5% vs.
13.1%, suggesting a better efficacy of bevacizumab in combination with IFN-α, although no statistical difference was obtained in either OS (23.3 months vs. 21.3 months and 18.3 months vs. 17.4 months).
In the international multicenter clinical study of pazopanib versus placebo for mRCC (Sternberg et al.), 233 patients were treated in first line, and significant differences were obtained in PFS of 11.1 months and 2.8 months, respectively, and ORR of 30% and 3%, respectively.
Therefore, all three of these tyrosine kinase inhibitors (TKI) of the vascular endothelial growth factor receptor (VEGFR) were recommended by the NCCN panel as Class 1 therapy for the first-line treatment of patients with mRCC.
The ARCC study randomized 626 previously untreated patients with high-risk mRCC into three treatment groups: the IFN-α group, the tesilomorph group, and the tesilomorph + IFN-α group. As a result, the OS of the tesilomox group was 10.9 months, which was significantly higher than that of the IFN-α group at 7.3 months, and the PFS of both was 5.5 months and 3.1 months, respectively. In contrast, the combination treatment group did not improve OS and PFS, but instead increased toxicity. Therefore, the panel recommended the mTOR inhibitor tesilimox as Class 1 for first-line treatment in high-risk patients with mRCC.
The direct comparison between sorafenib and IFN-α for first-line treatment of mRCC only has results from phase II trials, with PFS of 5.7 and 5.6 months in the two groups, respectively, and similar side effects, but quality of life was better in the sorafenib group than in the IFN group; and the vast majority of patients who progressed after IFN treatment crossed over to receive sorafenib, which may have led to prolonged PFS in the IFN-α group, thus suggesting that potential clinical benefit of sorafenib in the first-line treatment of mRCC. Therefore, the NCCN panel also recommended sorafenib as first-line treatment, but the recommendation level was only 2A.
In summary, the current NCCN guidelines recommend first-line treatment for metastatic or unresectable ccRCC including: sunitinib, or pazopanib, or bevacizumab + IFN (all recommended as Class 1); and high-dose IL-2 and sorafenib (all recommended for selective patients), all recommended as Class 2A; tesilomox (recommended as Class 1 for high-risk patients; Class 2 for other patients); and best supportive care. B recommendation); best supportive care (BSC); and the NCCN encourages patients to actively participate in clinical trials.
V. Follow-up treatment of metastatic or unresectable clear cell predominant renal cell carcinoma
The TARGET study used sorafenib or placebo as a follow-up treatment option after failure of first-line therapy (overwhelmingly cytokine therapy). The resulting PFS was 5.9 (sorafenib) and 2.8 months (placebo) for the two groups, respectively. The phase III study of pazopanib versus placebo conducted by Sternberg et al mentioned above also included 202 patients with mRCC who had failed cytokine; in this group of second-line treated patients, the PFS was 7.4 and 4.2 months in the pazopanib and placebo groups, respectively. In addition Motzer et al. also obtained PFS benefit for all mRCC patients after cytokine failure in second-line treatment with sunitinib. Thus, the guidelines recommend all of these TKI drugs as Class 1 follow-up after cytokine failure.
So how do you proceed with second-line options after first-line TKI failure? The guidelines also provide evidence-based medicine. The RECORD-1 study establishes the status of the mTOR inhibitor everolimus as a follow-up treatment after first-line TKI failure for mRCC. The phase III study compared the efficacy of everolimus with placebo in 410 patients with mRCC who had failed sunitinib or sorafenib. The PFS in the two groups was 4.9 (everolimus) and 1.9 months (placebo), respectively, with a significant difference in efficacy, making everolimus a Class 1 recommendation for follow-up therapy after failure of a first-line TKI.
Replacement of one TKI for treatment after failure of another TKI can still benefit patients, for example, sorafenib and sunitinib sequential treatment for mRCC did not show complete cross-resistance, but most of the relevant studies were retrospective and not as evidence-based as phase III trials, so NCCN recommended sorafenib and sunitinib as class 2A for follow-up treatment after failure of other TKI, while pazopanib Data for treating patients after failure of other TKI are not yet available, so it is only a Class 3 recommendation.
Other agents including tesilomox, bevacizumab, IFN, or IL-2 are also available as options for follow-up therapy, but at a much lower level of evidence.
In summary, current NCCN guideline recommendations for follow-up treatment of metastatic or unresectable ccRCC include: everolimus (Class 1 recommendation after TKI failure); sorafenib or sunitinib (Class 1 recommendation after cytokine failure; Class 2A recommendation after TKI failure), pazopanib (Class 1 recommendation after cytokine failure; Class 3 recommendation after TKI failure), tesilomoside or bevacizumab (Class 2A recommendation after cytokine failure; Class 2B recommendation after TKI failure); and IFN or IL-2 (both Class 2B recommendations); best supportive care; patients are likewise encouraged to actively participate in clinical trials.
VI. Treatment of metastatic or unresectable non-clear cell predominant renal cell carcinoma
In the ARCC study mentioned above, subgroup analysis showed that tesilomox was effective not only in clear cell carcinoma but also in non-clear cell carcinoma, especially in high-risk non-clear cell carcinoma patients. Therefore, tesilomox is recommended by the NCCN guidelines as a Class 1 treatment for high-risk non-clear cell carcinoma patients and a Class 2A treatment for non-high-risk patients.
In addition, based on the available data, patients with non-clear cell carcinoma can also benefit from treatment with sunitinib or sorafenib, so both of these drugs are recommended as Category 2A treatment for non-clear cell predominant renal cell carcinoma, while pazopanib has not been studied in patients with non-clear cell carcinoma and is only a Category 3 recommendation in the guidelines.
Another option recommended as a Class 3 is the epidermal growth factor receptor (EGFR) TKI agent erlotinib, which Gordon et al. showed achieved an ORR of 11% and a disease control rate (DCR) of 64% with an OS of 27 months for papillary renal cell carcinoma. Erlotinib’s recommendation as a Category 3 is another update to the new edition of the guidelines.
Gemcitabine in combination with doxorubicin chemotherapy for renal cell carcinoma with sarcomatoid differentiation has shown some efficacy and is also recommended as a Category 3 treatment in the NCCN guidelines.