Diagnosis, follow-up updates and changes in presentation
Molecular Diagnosis
The 2014 NCCN guidelines place more emphasis on molecular diagnosis. It is recommended that sufficient tissue be used for molecular subtype classification and, if possible, repeat biopsies be considered if necessary. For fewer tissue samples, especially in advanced NSCLC, immunohistochemical (IHC) testing should give way to molecular diagnosis. In most cases, detection of one marker for squamous carcinoma (p63) and one marker for adenocarcinoma [thyroid transcription factor 1 (TTF-1)] is sufficient.
For adenocarcinoma, large cell carcinoma, or unclassified NSCLC, ALK testing is recommended for category 1. The population characteristic of ALK rearrangement has been removed from “tendency to be present in young and advanced NSCLC patients” and the test is not limited to lung adenocarcinoma. Epidermal growth factor receptor (EGFR) ± ALK is recommended as two targets for multiplex or next-generation sequencing in NSCLC, especially in patients with squamous and mixed histologic types who do not smoke or have small specimens (Figure 1). For patients with EGFR mutations and ALK rearrangement negativity, other mutation testing may be considered.
As sensitive mutations for tyrosine kinase inhibitors (TKI), testing for the L861 mutation in EGFR exon 21 and the G719 mutation in exon 18 is recommended. transformation, and epithelial mesenchymal transition (EMT) were associated.
Follow up
After 3-6 months of low-dose CT follow-up for non-solid or partially solid nodules larger than 10 mm, the conditions for consideration of surgical resection added “increased solid component” in addition to increased size.
For multiple pulmonary lesions, “small subsolid nodules with slow growth” was added to the list of observable symptomatic low-risk patients, and “accelerated growth of subsolid nodules or increased solid component or increased deoxyglucose (FDG) uptake” was added to the list of high-risk patients considered for treatment. “. Patients with stage I-IV NSCLC without clinical or imaging manifestations were monitored by history and physical examination and chest CT (enhanced or plain) every 6-12 months for 2 years, followed by annual monitoring by history and physical examination and chest CT plain, and the recommendation was changed from 2B to 2A.
Expression change
“The expression “supportive care” was changed to “integrate palliative care”. The expression “marginally resectable” was changed to “possibly resectable”.
Medical treatment
Targeted therapy
The 2014 NCCN guidelines for medical therapy place greater emphasis on the use of molecularly targeted therapeutics. The guidelines summarize the targeted agents for patients carrying genetic alterations (driving events) (Table 1). The treatment process for ALK-positive patients is refined, and recommendations are also categorized, especially for post-progression therapy. This fully demonstrates that individualized therapy guided by molecular markers is the direction of treatment for lung cancer.
First-line treatment
For patients with EGFR-sensitive mutation-positive lung adenocarcinoma, large cell carcinoma or unclassified NSCLC, the guideline adds a category 1 recommendation for afatinib if EGFR gene mutation is detected before first-line chemotherapy. If an EGFR mutation is identified during first-line chemotherapy, treatment is modified to “interrupt or complete the established chemotherapy regimen and initiate or add erlotinib or afatinib therapy (Class 2B)” (Figure 2). The guideline adds “Erlotinib should not be used as first-line therapy for patients with negative or unknown EGFR mutations.”
Second-line therapy
For patients with EGFR-sensitive mutations in adenocarcinoma, large cell carcinoma, and unclassified NSCLC, the guidelines add the option of second-line treatment with afatinib for asymptomatic progression, symptomatic isolated or multiple brain metastases, and systemic isolated lesion progression, based on the results of the LUX-Lung1 study (Figure 2). According to the CALGB30406 study, erlotinib may be given for cancerous meningitis. In case of systemic multiple metastases, a platinum-containing two-drug regimen ± bevacizumab ± erlotinib may be given. For NSCLC patients with functional status score (PS) 0 to 2 EGFR mutation and ALK-negative or unknown status, second-line therapy adds the option of gemcitabine.
Third-line therapy
For patients with NSCLC with a PS score of 0 to 2 who have not had gemcitabine, third-line therapy adds the option of this drug. The guideline adds “Docetaxel, pemetrexed (for nonsquamous NSCLC), and gemcitabine are recommended as Class 2B if the patient has not received erlotinib or crizotinib and the following drugs in first and second lines.”
Maintenance therapy
The new guidelines weaken the recommendation for maintenance therapy by removing the option to “continue current regimen until disease progression.” For patients with EGFR- and ALK-negative or unknown NSCLC, gemcitabine prodrug maintenance has been changed from a Class 2A to a Class 2B recommendation. Switching maintenance of pemetrexed or erlotinib in non-squamous NSCLC and docetaxel or erlotinib in squamous cancer was also recommended from Category 2A to Category 2B.
Surgical Procedures and Adjuvant Therapy
Evolution of VATS status
The beginnings of television-assisted thoracoscopic surgery (VATS) date back to 1912, but the success of thoracoscopic anatomical lobectomy was achieved only in 1992, only 20 years ago now. In this short 20-year period, VATS has not only become technically mature and widely used, but more importantly, a wealth of evidence has confirmed oncologically that VATS is as effective or better than open pneumonectomy for early-stage non-small cell lung cancer (NSCLC).
The National Comprehensive Cancer Network (NCCN) guidelines first included VATS in the 2006 edition, stating that “VATS may be a viable surgical option for resectable lung cancer as long as it does not violate oncologic standards of care and principles of thoracic surgical resection. The tone of this statement is one of moderation and hesitation. This is because, although studies have shown that VATS has some advantages over open surgery, such as causing less acute and chronic postoperative chest pain, shorter hospital stays, lower postoperative complications and mortality, and less risk of intraoperative bleeding or local regional recurrence. In addition, VATS allows for a faster return to self-care after hospital discharge in elderly and high-risk patients, but there was still much dissent and debate.
With the emergence of more evidence-based evidence in favor of VATS and the finding that patients are more likely to receive and complete a full course of adjuvant chemotherapy after VATS, the 2010 edition of the guidelines was revised to read “VATS for NSCLC is a reasonable and acceptable procedure if the patient has no anatomic or surgical contraindications and as long as it does not violate oncologic standards of care and principles of thoracic surgical resection. The 2010 edition of the guideline was revised as “VATS for NSCLC is a reasonable and acceptable procedure if the patient has no anatomical or surgical contraindications, provided that it does not violate the standards of tumor treatment and the principles of thoracic surgery. Back then, the treatment of early stage NSCLC was still mainly open surgery.
The 2014 edition of the guideline was further updated to “VATS or other minimally invasive pneumonectomy for early-stage NSCLC is highly recommended if the patient has no anatomical or surgical contraindications, as long as it does not violate oncologic standards of care and principles of thoracic surgical resection”. It is easy to see that VATS has become the mainstream procedure for early-stage NSCLC due to the advancement and application of VATS technology and the increasing evidence of evidence-based medicine, and it is also easy to understand that the status of open surgery will further decline.
Postoperative adjuvant therapy
The level of evidence for adjuvant chemotherapy has been changed from category 2B to 2A for patients with stage IB~IIA NSCLC with negative surgical margins (R0) and high risk factors (tumor hypofractionation, >100px, dirty pleural invasion and incomplete lymph node sampling). In stage II to IIIA patients with positive surgical margins, adjuvant therapy for R1 (positive microscopic margins) and R2 (positive sarcoid tumor margins) was originally described in a footnote and is now specifically distinguished in the flow chart in the guidelines. Stage II R1 patients are recommended for re-excision + chemotherapy or (sequential or concurrent) radiotherapy, and R2 patients are recommended for re-excision + chemotherapy or concurrent radiotherapy. Stage IIIA R0 patients were explicitly recommended for adjuvant chemotherapy as category 1, with sequential radiotherapy recommended for N2 patients; sequential or synchronous radiotherapy for R1 patients; and synchronous radiotherapy for R2 patients (Figure 3).
Radiation therapy
With or without prophylactic irradiation
The RTOG9311 trial was conducted to study the target area of radiotherapy for NSCLC and demonstrated that no prophylactic irradiation did not reduce the efficacy, the recurrence rate in the field was slightly higher, irradiation of only positive lesions helped to increase the irradiation dose and reduce toxicity, which in turn improved the long-term survival rate, and induction chemotherapy could reduce the tumor volume to a certain extent and create conditions for dose boosting.
Radiotherapy for early-stage NSCLC
For stage I NSCLC, radical surgery ± adjuvant chemotherapy is still the standard treatment modality, and the new version of the guidelines has not made too many changes, with the following main update points.
Surgery is the treatment of choice for stage IA NSCLC. For those who cannot operate or refuse surgery for medical reasons, radical radiotherapy, including stereotactic radiotherapy (SABRT), is feasible, with a recommended biological dose greater than 100 Gy.
For patients with stage IB or II inoperable for medical reasons, lymph node status was added to the treatment recommendations, with radical radiotherapy including SABRT recommended for those with N0, followed by adjuvant chemotherapy for those at high risk (category 2B); radical chemoradiotherapy was recommended for those with N1 (Figure 4). Results from clinical trials have confirmed that radiotherapy is superior to radiotherapy alone for inoperable early-stage NSCLC patients, and concurrent radiotherapy is superior to sequential radiotherapy.
Radiotherapy for locally progressive and advanced NSCLC
The standard treatment for stage III inoperable patients is radical concurrent radiotherapy. The RTOG0617 study compared standard-dose (60 Gy) radiotherapy with high-dose (74 Gy) radiotherapy in 464 patients with stage III NSCLC, who also received paclitaxel and carboplatin chemotherapy, and showed that standard-dose radiotherapy better controlled tumor progression and spread and even improved overall survival, and the high-dose group Patients had a 56% increased risk of death and a 37% increased risk of local tumor progression. Possible reasons for the poorer outcome in the high-dose group are increased radiation to the heart or toxic reactions that have not been reported. The proportion of reported side effects was similar between the two doses of radiotherapy, but the incidence of esophagitis was higher in patients in the high-dose group (21% versus 7%).
This study confirms that the standard dose of radiation for concurrent radiotherapy in stage III NSCLC remains 60 Gy. A meta-analysis confirms that hyperfractionated radiotherapy regimens improve survival, and a randomized study (RTOG1106) is evaluating individualized dose increases for hyperfractionated radiotherapy.
The new guidelines differentiate treatment recommendations for those with recurrent mediastinal lymph nodes based on whether or not they have received prior radiotherapy, and add recommendations for systemic chemotherapy for patients who have received prior radiotherapy. The description of radical concurrent radiotherapy has been changed to “If full dose chemotherapy is not given concurrently with radiotherapy at the time of initial treatment, add an additional 2 cycles of full dose chemotherapy (note: previously 4 cycles).” The recommendation for weekly paclitaxel+carboplatin regimen was changed from Category 2B to Category 2A in the synchronous radiotherapy followed by chemotherapy regimen. Patients with stage IV M1b isolated site metastases, T1~2N0~1 or T3N0 patients were added the option of SABRT to the lung lesion after chemotherapy.