Non-small cell lung cancer 2010 NCCN guideline update
The Guidelines adopt the latest TNM staging recommended by the International Association of Lung Cancer (IASLC) in 2009. The number of NSCLC cases analyzed in this staging reached 68,463. The revision is shown in T and M staging, with no change in N staging, and details include: ①Tumor ≤7cm is T2, >7cm is T3, while T1 and T2 are each divided into two subgroups a and b, i.e. T1a ≤2cm, T1b >2cm and ≤3cm, T2a >3cm and ≤5cm, T2b >5cm and ≤ The overall staging was also updated accordingly, with T2aN0M0 and T2aN1M0 being upgraded from stage IB and IIB to stage IIA, and T4N0M0 and T4N1M0 being upgraded to stage IIA. T2aN0M0 and T2aN1M0 were changed to stage IIA, and T4N0-1M0 was upgraded from stage IIIB to stage IIIA.
The new TNM staging better demonstrated the prognostic difference between different stages, but because it was based on retrospective analysis, the impact on prognosis needs to be further verified by subsequent studies.
Treatment of advanced NSCLC
Surgical resection
Radical surgery is the treatment of choice for patients with advanced NSCLC, but for patients with poor local root conditions who cannot undergo radical surgery, radical radiotherapy or limited surgical resection can improve their 5-year life rate. Therefore, the Guidelines recommend that radical radiotherapy or limited surgical resection is feasible for patients with stage I and II mediastinal lymph node negativity who are inoperable for medical reasons (Class 2A recommendation), and the guidelines for surgery and radiotherapy are lifted. In particular, limited surgical resection includes: segmental lung resection (preferred) or wedge resection, which is used only for three special groups: (1) those who can save little lung tissue or cannot undergo radical surgery due to other important comorbidities; (2) those who have a peripheral nodule ≤2 cm and fit at least one of the histological types of simple bronchoalveolar carcinoma or CT showing ≥50% glassy nodule changes; (3) those who have imaging follow-up evidence of tumor Doubling time ≥ 400 days (recommended for category 2B).
Adjuvant treatment
The Guidelines further clarify the applicable population for postoperative adjuvant therapy. The Guidelines no longer recommend adjuvant chemotherapy as a treatment option for stage IA and non-high risk stage IB patients. Patients with positive postoperative margins in stage IA are still considered advanced in practice, and secondary resection has become the preferred treatment modality; direct synchronous chemoradiotherapy is only recommended for category 2B, and adjuvant chemotherapy is no longer recommended after either surgery or chemoradiotherapy. Regarding the treatment of positive cut margins in stage IB and adjuvant chemotherapy in stage II, there is no update in the Guideline.
High-risk IB has added tumor >4cm, dirty pleural involvement, and Nx (unable to evaluate lymph node morphology) to the original base. Based on the results of the subgroup analysis of the CALGB9633 study, the guidelines recommend stopping postoperative adjuvant chemotherapy for people with tumors >4cm. The involvement of the dirty pleura suggests that the surgical margins are close to the tumor, which can lead to inadequate resection, while the Nx suggests that the lymph nodes can be poorly cleared and that the risk of recurrence is higher in this group than in non-high-risk stage IB patients, thus adjuvant chemotherapy is recommended, but the guidelines do not provide primary evidence-based evidence.
Regarding concurrent radiotherapy for stage IIA and IIB patients with adverse factors (inadequate lymph node clearance, extracapsular invasion of lymph nodes, positive lymph nodes at multiple sites, and positive cut margins) and negative cut margins, the recommendation level in the Guideline was lowered to category 3 due to the divergent opinions of the panel.
Treatment of T3 Stage II
The concept of T3 stage II has been expanded in the Guidelines to include tumors >7 cm, satellite nodules in the same lobe (formerly T4) and T3 that directly invade the chest wall or mediastinal pleura. For T3 stage II lung cancer invading the chest wall, mediastinum or near the trachea, lobectomy or total pneumonectomy and mediastinal lymph node dissection are preferred if the preoperative evaluation is resectable. If the preoperative evaluation is unresectable, concurrent radiotherapy is preferred. After 2-3 cycles of chemotherapy and 40Gy radiotherapy, the resectability of surgery is re-evaluated and surgery is performed if resectable, and radiotherapy is continued if unresectable.
Treatment of partial early stage NSCLC
Partial early stage NSCLC mainly refers to stage IIIA and IIIB tumors, including invasion of the chest wall, near the airway or important organs of the mediastinum (T3-4), positive lymph nodes at stations N2 or N3, as well as supraglottic sulcus tumors and isolated pulmonary nodules.
Treatment of stage IIIA
Stage IIIA NSCLC is capable of surgical radical treatment, and multidisciplinary combination therapy remains the recommended form of treatment, and the Guideline update focuses on discussing the best form of treatment.
For patients with T4N0-1 stage IIIA, the feasibility of surgery should first be evaluated by experienced internists, and the preferred treatment for resectable tumors is surgery (category 1 recommendation), with the option of preoperative neoadjuvant chemoradiotherapy or chemotherapy (category 2A recommendation) to achieve stage reduction and reduce potential micrometastases and improve disease-free life. In case of complete resection, postoperative adjuvant chemotherapy is considered. In case of positive cut margins, postoperative radiotherapy and platinum-containing regimen chemotherapy are recommended.
There are two types of N2 lymph node positivity, one is “inevitable” N2 positivity, i.e. not detected before surgery but found positive in postoperative pathology; the other is evaluated as N2 positivity before surgery. As partial recurrence is the rarest form of recurrence, radiotherapy should be started as early as possible. In practice, the postoperative radiotherapy field of local centers includes the cut edge to increase partial recurrence. For this reason, the word “mediastinum” in the original postoperative “mediastinal radiotherapy” has been deleted and replaced by “postoperative radiotherapy” in the Guidelines. For those who have been evaluated as N2 positive before surgery, the guideline rediscusses the treatment of T3N2M0. For T3>7, surgical feasibility evaluation is still recommended after neoadjuvant chemoradiotherapy or induction chemotherapy, while for other T3N2M0, radical simultaneous chemoradiotherapy is recommended without stopping surgical feasibility evaluation midway. Studies have demonstrated that induction chemoradiotherapy followed by internal resection does not improve overall survival in N2 positive NSCLC, and subgroup analysis showed that patients who received lobectomy lived better than direct synchronous chemoradiotherapy, but those who had total pneumonectomy lived worse than direct synchronous chemoradiotherapy. Thus, the Guidelines no longer recommend considering surgery for this localized group of patients.
Treatment of Stage IIIB
The Guide adopts the new TNM staging fragment, and the expression of stage IIIB NSCLC has been updated accordingly, mainly including: resectable tumors without satellite foci (T3~4N0~1M0) enter stage IIB or IIIA, tumors with pleural effusion enter stage IV, tumors without pleural effusion, unresectable tumors and N3 tumors remain stage IIIB, and the disposition of these cases is fundamentally different from the 2009 version of NCCN The treatment of these cases is fundamentally different from the 2009 edition of NCCN guidelines. The treatment of NSCLC with resectable satellite foci, depending on the lung lobe in which the satellite foci are located, enters stage IIB, IIIA, or IV, and the treatment of these cases is described in the local lung nodules.
Treatment of supraglottic sulcus tumor
Supraglottic sulcus tumors are listed separately because of their special status. Tumors that directly invade the spine or spinal canal, the superior trunk of the brachial plexus (cervical 8 or above), or encircle the subclavian artery are considered T4, whereas in the absence of such evidence they are considered T3. Because it is sometimes difficult to distinguish between T3 and T4, the 2009 edition of the NCCN guidelines does not treat them differently. In practice, T3 supraclavicular sulcular lung tumors are clearly resectable, and therefore, the guideline lists a separate treatment process for this local tumor, which is synchronized chemoradiotherapy preceded by surgical resection and sequential adjuvant chemotherapy. stage T4 supraclavicular lung tumors are divided into two groups, resectable and unresectable, and the subsequent treatment process is different from the 2009 NCCN guideline.
Disposition of pulmonary nodules
Although metastatic nodules in the lungs are called “metastases”, they have a different prognosis than malignant plasma fluid or other organ metastases, and those that can be surgically resected have the potential for cure. Based on the new staging, the Guidelines subdivide metastatic nodules in the lung into three types: the same lobe as the primary site (T3), the same lung but a different lobe (T4), and contralateral intrapulmonary metastases (M1a), and propose treatment guidelines for each.
For the first two, if the primary focus is resectable, the Guidelines recommend surgery and adjuvant chemotherapy for those with negative margins after surgery, and concurrent chemoradiotherapy for those with positive margins who can tolerate it. Regarding contralateral intrapulmonary metastases, the Guidelines recommend two forms of treatment. One is preoperative neoadjuvant therapy (including induction chemoradiotherapy or induction chemotherapy), and postoperative adjuvant chemotherapy can be monitored for those with negative margins or selected based on the patient’s sensitivity and tolerance to preoperative chemotherapy; for those with positive margins, if preoperative radiotherapy has not been administered, postoperative radiotherapy should be administered first, otherwise remedial chemotherapy should be stopped. The other is direct surgical treatment with adjuvant chemotherapy for those with negative cut margins after surgery and sequential chemotherapy with synchronized chemoradiotherapy for those with positive cut margins. For isolated lung metastases, if both the primary and metastatic foci are curable, the Guidelines recommend that they be treated according to the primary cancer discrimination.
Treatment of recurrent and metastatic NSCLC
Since the treatment and prognosis of malignant pleural effusion or pericardial effusion is closer to that of early NSCLC, the new TNM staging fragment classifies it as stage IV, and its disposal criteria are updated with the step.
Isolated organ metastasis
Numerous studies have demonstrated that isolated brain metastases can benefit from surgery, and the addition of whole brain radiotherapy (WBRT) extends the total life span, thus the Guidelines classify surgical resection of brain metastases + WBRT as a Class 1 recommendation. A meta-analysis showed that for patients with one to three brain metastases, WBRT followed by planar targeted radiotherapy (SBRT) could extend total life but may increase neurological damage, for which there is insufficient evidence, and therefore the Guidelines recommend WBRT followed by SBRT only as a category 2B recommendation. For patients who cannot tolerate surgery for brain metastases, SBRT ± WBRT is still recommended (category 2A recommendation).
Isolated adrenal metastases account for about 33% of lung cancer cases, and the expert group is divided on whether metastases can be resected first, so the guideline is still recommended as category 3. In addition, since radiotherapy (3D conformal radiotherapy or SBRT) or radiofrequency melting can provide positive survival benefit for inoperable advanced lung cancer, the guideline changes the treatment of adrenal metastases from “resection” to “partial treatment”, that is, in addition to surgery In addition to surgery, treatment options such as radiotherapy or radiofrequency melting are available.
For patients with anatomically resectable but otherwise inoperable metastases, the Guidelines recommend SBRT for the primary site, but only as a Category 2B recommendation due to the lack of primary clinical evidence. For those who are anatomically unresectable, there are no updates to the Guidelines.
First-line treatment
In recent years, with the publication of many clinical studies, the choice of first-line treatment for stage IV NSCLC has expanded significantly. The Guidelines make recommendations for first-line treatment based on the patient’s physical condition (PS).
There are five recommendations for early-stage NSCLC with PS of 0 to 1: chemotherapy (Class 1 recommendation), bevacizumab + chemotherapy for the right population (Class 2A recommendation), pemetrexed + cisplatin for the right population (Class 1 recommendation), cetuximab + vincristine/cisplatin (Class 2B recommendation), and erlotinib for those with epidermal growth factor receptor (EGFR) taper (Class 2A recommendation). In the first four recommendations, the guideline has been revised based on updated study data on the local suitable population and recommendation level, for example, “no brain metastasis” was removed from the suitable population for bevacizumab, it was clarified that pemetrexed + cisplatin is not suitable for patients with squamous cancer, and the recommendation level of cetuximab combined with chemotherapy was lowered to category 2B. The Guidelines again clearly recommend the use of erlotinib for those with EGFR progression. A number of studies have demonstrated that EGFR progressives treated with gefitinib or erlotinib in the first line can achieve better outcomes. The IPASS study from Asia showed that the risk of disease arrest was lower in EGFR progressives treated with first-line gefitinib than in paclitaxel+carboplatin, but the opposite was true for those without progressions.
Regarding early-stage NSCLC with PS ≥ 2, there are two main changes in the Guidelines. First, for patients with PS of 2, platinum-based two-drug combination chemotherapy can be chosen, but adequate amounts of cisplatin should be given selectively, as this local population can be less tolerant of chemotherapy. Second, the IPASS study included patients with PS=2 in early-stage NSCLC, and this local population may still benefit from first-line use of gefitinib if EGFR progression is present. In addition, a phase III study in Japan showed that the benefit of first-line gefitinib was also present in people with PS 3 to 4. Because gefitinib is not available in the United States, the Guide recommends comparable first-line erlotinib for patients with early-stage NSCLC with EGFR progression with PS ≥ 2. From the Guidelines, erlotinib is indicated for patients with various PS scores with EGFR mutations, but the consequences of several studies have shown that patients with KRAS mutations do not benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, thus the Guidelines re-emphasize that treatment other than erlotinib should be considered first regarding this local population.
Maintenance therapy
As first-line chemotherapy continues for only four to six cycles, whether to follow up with probation or maintenance therapy has become one of the focuses of attention in recent years, and many clinical trials have emerged. The “guidelines” based on the results of these studies, maintenance treatment or follow-up are feasible, and maintenance treatment is divided into two categories: ① continuous maintenance treatment, refers to the first line of treatment after 4-6 cycles, if no disease stop, the use of up to one first-line treatment was used to maintain treatment; ② change maintenance treatment, refers to the first line of treatment after 4-6 cycles, if no disease stop, the use of another drug not included in the first-line (ii) maintenance therapy with another drug not included in the first-line regimen after 4-6 cycles of first-line therapy if there is no disease arrest. There is no evidence to support the use of traditional cytotoxic drugs for ongoing maintenance therapy. Based on the ECOG4599, FLEX, and JMEN studies, the guideline recommendations for ongoing maintenance therapy include: (1) bevacizumab (Class 1 recommendation), but only after 4-6 cycles of platinum-containing two-drug chemotherapy combined with bevacizumab; (2) cetuximab (Class 1 recommendation), but only after 4-6 cycles of cisplatin + vincristine combined with cetuximab; and (3) pemetrexed (Class 2B category recommendation), only for patients with non-squamous cancer. Regarding maintenance therapy with drug replacement, the guideline recommendations are not high: (1) pemetrexed (Class 2B recommendation), only for patients with non-squamous cancer; (2) erlotinib (Class 2B recommendation); and (3) docetaxel (Class 3 recommendation). Evidence for the first two recommendations came from the JMEN study and the SATURN study. Evidence for docetaxel maintenance therapy is lacking, and the expert panel was more divided.
Second-line treatment
Erlotinib has been recommended by the Guidelines for first-line treatment in patients with EGFR progression, so there is no primary level of evidence-based medical evidence to inform the choice of treatment options after failure. Since platinum is the main drug used for the treatment of NSCLC, its efficacy is obvious. Thus, the panel thought that a platinum-containing two-drug combination regimen could be chosen after discontinuation of first-line erlotinib therapy (Class 2B recommendation). In addition, subgroup analysis of the BR.21 study showed that patients with EGFR progression could benefit from second-line treatment with erlotinib, and the benefit population included patients with a PS of 3. Therefore, the panel thought that patients with PS=4 could also benefit from it, but only in the population with EGFR mutation.
Pemetrexed has comparable efficacy to docetaxel in second-line treatment, but with fewer adverse effects, and the Guidelines state that pemetrexed is superior to docetaxel for the treatment of patients with adenocarcinoma and large cell carcinoma.
The clinical theory guidelines developed by the National Comprehensive Cancer Network (NCCN) are currently the main reference guidelines for oncology treatment in China. With the release of the latest evidence-based medical evidence for non-small cell lung cancer (NSCLC), the NCCN Clinical Theory Guidelines for Non-Small Cell Lung Cancer (2010 Edition) (hereinafter referred to as “the Guidelines”) have also been updated accordingly. A brief overview of the updates to the Guidelines is provided above.
Screening and Follow-Up
There are few amendments to this part of the guideline, mainly including three aspects: ① the chance of lymph node metastasis is very low in peripheral isolated carcinoma nodes to be operated, so preoperative invasive examination should be prevented, thus the guideline recommends intraoperative bronchoscopy for this local population, but for prudence, it is limited to stage IA (peripheral T1abN0) population; ② bronchial endoscopic ultrasound-transmural needle aspiration (EBUS-TBNA) (ii) bronchial endoscopic ultrasound-transmural needle aspiration biopsy (EBUS-TBNA) has been shown to be superior in disease staging and diagnosis of mediastinal lesions, with higher sensitivity and specificity compared with PET/CT, and therefore the guideline recommends adding this test to the pre-treatment evaluation of stage I and II patients (Class 2B recommendation); (iii) because there is no strong evidence to support the use of PET or brain MRI for routine follow-up, the guideline does not recommend either test. The Guidelines do not recommend these two tests for routine follow-up.
After the release of the new TNM staging for NSCLC, the 2010 edition of the Guidelines is “a long time coming”. Based on some primary evidence-based medical evidence, the Guidelines recommend many new treatment modalities, but there is still a considerable part of the unconsensus, and more clinical trials are needed to verify and support them. Of course, international scholars should also selectively bear the Guidelines update and refer to more evidence from international studies when developing the Chinese version of the Guidelines to better apply to the Chinese population.