Review and interpretation of the series of lung cancer surgery studies of the Japanese Clinical Oncology Research Group

Excerpt

Surgical resection is currently the most effective treatment for

According to data from the National Cancer Center, lung cancer is the malignant tumor with the highest incidence and death rate associated with malignant tumors

In response, the Japan Clinical Oncology Group (JCOG) launched a prospective, multicenter, observational JCOG0201 study in 2002 to investigate the feasibility

I.

From December 2002 to May 2004, 811 patients with peripheral stage I.

Survival data from the JCOG0201 study were first reported in 2013, with 5-year survival and 5-year recurrence-free survival (RFS) of 90.

As the pioneering work of JCOG's lung cancer surgery series, the results of JCOG0201 are based on standard lobectomy, although there is no direct comparison with the advantages and disadvantages of sub-lobectomy, but it enlightens the experimental design of follow-up related studies and plays a key role

II.

The JCO0804 study was a single-arm validated clinical trial evaluating the efficacy and safety of lobectomy (wedge resection and lung segment resection) in peripheral lung cancers with GGO-predominant (tumor length ≤ 2 cm, CTR ≤0.

Between 6 May 2009 and 26 April 2011, 333 patients from 51 centers in Japan were included in the study, of which 314 patients who eventually underwent sub-lobectomy were assessed for primary endpoints, including 258 cases of wedge resection and 56 cases of lung segment resection; The median tumor length and diameter above the lung window is 1.

With more than 50% of pure ground-glass nodules (PGGNs) included, the results of the JCOG0804 study were ideal and met the expectations

Another question is that since the patients in the JCOG0804 study had excellent long-term prognosis, it is debatable whether surgery is really needed for small nodules with a CTR of ≤ 0.

3.

The JCOG1211 study was also a non-randomized, one-arm validation trial to assess the effectiveness of lung segment resection in clinical stage T1N0 GGO-led lung cancer other than the patient population studied in JCOG0804, which requires hilar, interlobar, and intrapulmonary lymph node dissection, allowing for an additional 1 to 2 wedge resections, and the primary endpoint of the study was also 5 years OF RFS

Enrollment ended in 2015 and enrolled 390 patients

JCOG1211 is also an imaging-guided study of surgical resection of early lung cancer, and its main results not only re-verify that for GGO-dominated lung cancer, subpulmonary lobectomy with sufficient resection of the incision margin is completely sufficient, but also suggests that future preoperative imaging-based evaluation may directly determine the scope of resection of GGO-based pre-primary early adenocarcinoma without waiting for intraoperative frozen pathological results

During the enrollment of the JCOG1211 study, 3-dimensional computed tomography bronchography and angiography (3D-CTBA) were further promoted in lung segment resection surgery, and the identification and treatment of intersegial planes was continuously improved.
The quality of pulmonary segment resection is bound to improve
compared to the JCOG0802 study.
However, when performing lung segment resection for lung cancer with a tumor diameter of more than 2 cm, it is more challenging
to achieve qualified margin control than small lung cancer within 2 cm.
The safety results of the JCOG1211 study help us to revisit the practical benefits of pulmonary segment resection over lobectomy based on the JCOG0802 study, and look forward to the official publication
of the results.
"

4.
JCOG0802 research

1.
Study design: The JCOG0802/WJOG4607L study was a multicenter, randomized, controlled, non-inferior study that focused on comparing the efficacy of lung segment resection and lobectomy on peripheral radiological invasive adenocarcinoma (tumor length ≤ 2 cm, 0.
5 < CTR≤1), with the primary endpoint of the study being 5-year survival.
<b10> Due to the non-inferior design of the trial, when lung segment resection is not inferior but not superior to lobectomy at the primary endpoint, it is also necessary for pulmonary segment resection to be superior to lobectomy in terms of respiratory function 1 year after surgery to determine that lung segment resection can be used as a standard surgical procedure
.

Two key attributes of the JCOG0802/WJOG4607L study design deserve our attention, one is that unlike the JCOG0804 and JCOG1211 studies, the JCOG0802/WJOG4607L study included radiological invasive adenocarcinoma, and the choice of different resection ranges for this type of adenocarcinoma may have an impact on the patient's long-term prognosis, and the results of the study will directly determine whether lung segment resection can continue as a compromise procedure or can be widely used; Second, although the research procedure requires intraoperative pathological confirmation at the time of secondary registration, the pathological results only determine whether the patient can finally be randomized into the group, without affecting the choice of surgical style, and the study is still to verify the feasibility
of selecting the surgical method according to the preoperative imaging characteristics.

2.
Interpretation of the results: from August 10, 2009 to October 21, 2014, a total of 1 106 patients (intended treatment population) from 70 centers in Japan were included, of which 422 patients over 70 years old (38.
2%); Adenocarcinoma 968 cases (87.
5%); 923 cases (83.
5%) of pTNM belonged to Stage I.
a (7th edition TNM staging); The median tumor length and diameter was 1.
6 cm (0.
6 to 2.
0 cm); 553 (50.
0%) pure solid tumor CTR=1; 554 patients underwent lobectomy and 552 patients underwent pulmonary segment resection; In the lung segment resection group, 22 patients were converted to lobectomy and 1 underwent wedge resection; The median prognosis follow-up time was 7.
3 years
.
Intent-to-treat analysis (ITT) showed that the five-year survival rates of patients in the lung segment group and the lobe group were 94.
3% and 91.
1%, respectively (HR=0.
663, 95% CI: 0.
474-0.
927, non-inferior unilateral P<0.
0001, and potent P=0.
0082), which was better than the lobe group<b11> 。 The advantages of pulmonary segment resection in the protocol analysis and treatment analysis were more obvious in terms of overall survival, with HR being 0.
597 (95% CI: 0.
419-0.
849) and 0.
574 (95% CI: 0.
407-0.
811), and 87.
9% and 88.
0% (HR=0.
998, 95% CI: 0.
753-1.
323, P=0.
9889) in 5 years, respectively, and the difference was not statistically significant
。 The percentage difference between the two groups of patients was 3.
5% (P<0.
0001) of forced expiratory volume in the first second of the first year after surgery, a statistically significant difference, but did not reach the expected predetermined threshold<b13> of 10%.
。 According to the criteria set out in the study protocol, lung segment resection should be the standard procedure
for small peripheral radiological invasive lung adenocarcinoma due to its efficacy over lobectomy in 5-year survival and significant advantages in lung function protection.
The JCOG0802/WJOG4607L study became the first randomised controlled trial to date to show that early-stage lung cancer lung segment resection was superior to lobarectomy in terms of overall survival, but there is still a lot of valuable information and controversies behind the encouraging results
.

First, whether lung segment resection can achieve thorough tumor resection
.
From the perspective of 5-year RFS, although there was no statistically significant difference between lung segment resection and lobectomy, 11% (n=58) of patients in the lung segment group had local recurrence, compared with only 5% (n=30) of patients in the lobe group, and the local recurrence rate in the lung segment group was almost twice that
of the lobe group.
In the local recurrence, there were no recurrences of surgical margins and bronchial stumps in the lobe group, while 11 cases of margin recurrence and 2 cases of bronchial stumps in the lung segment group; The number of patients with recurrence of hilar and mediastinal lymph nodes in the lung segment group was also more than that in the lobe group
.
Leaving aside the competitive risk of relapse from death events in the survival analysis (i.
e.
, additional death events in the lobe group may somehow reduce recurrence events), it is clear that segment resection of the lung segment in the JCOG0802 study still does not address the high local recurrence rate of sublobar resection
.
The possible reasons are that there is still room for improvement in the completion quality of some lung segment surgery, and the traditional single lung segment or joint double lung segment resection based on tomographic CT planning is not delicate enough at present, and it can be seen that 4 patients in the lung segment group have expanded the scope of resection or undergone secondary surgery
due to incomplete resection of the margin.
Up to 70 centers enrolled patients, and the quality of lung segment surgery by operators at different centers also varies, as evidenced
by the average length of lung segment surgery.
The second is the indication for pulmonary segment resection, 16 patients in the lung segment group in the JCOG0802 study switched to lobectomy because the hilar and/or mediastinal lymph node metastases
were confirmed during the operation.
From the perspective of controlling local recurrence, the incision margin is theoretically appropriate, but the fact that the cancer has metastasized (e.
g.
, interseg segmental lymph node positivity) and may metastasize [spread through air spaces (STAS) positive and high-grade adenocarcinoma] to high-risk nodules outside the margin range may require switching to lobectomy
.
On these issues, the JCOG0802 study lacks corresponding quality control measures
.

How we can perform a more thorough lung segment resection, we would like to make the following points
.
The first is to ensure the principles of oncology, Wu et al.
reported that the use of 3D-CTBA technology for thoracoscopic combined subsection can preserve more lung parenchyma and ensure safe margins
.
The preoperative planning of lung segment resection using three-dimensional reconstruction technology is centered on the lesion, not limited to the inherent intersegro plane, and the resection range of the target lung tissue is determined according to the tumor safety margin, and the incision margin can be more strictly controlled
.
At lobectomy, the removal of intra-lobe lymph nodes can reduce the rate of missed diagnosis of N1 lymph node metastasis, and chemotherapy in patients with N1 lymph node positive is expected to reduce the risk
of recurrence.
Similarly, when performing lung segment resection, the examination of intersegmental lymph nodes cannot be ignored, especially stage T1b lung cancer with a large invasive component, which has a relatively higher
probability of occult lymph node metastasis.
When rapid freezing pathology confirms the presence of intersegmental lymph node metastases, lobectomy is more conducive to the thoroughness of the procedure than intentional lung segment resection
.
In addition, since high-risk pathological components such as STAS and micro-papilla are risk factors for recurrence after pulmonary segment resection, it is more scientific and reliable
if the scope of resection can be determined before surgery or through the results of intraoperative frozen pathology.
The final results of another large multicenter randomized controlled trial, GALGB140503, similar to the JCOG0802 study, will be published in 2024 to verify that the disease-free survival time of sub-lobectomy (wedge resection or lung segment resection) of peripheral NSCLC is comparable to that of lobectomy, and it is believed that more valuable information
can be provided on this issue.

The second question is how to look at the differences in survival outcomes and causes of death between the two groups of patients regardless
of primary lung cancer.
The results of the JCOG0802 study showed that patients in the lobectomy group died slightly more from other diseases (n=52) compared with the lung segment resection group (n=27), in addition, patients who underwent lobectomy (n=31,6%) had more common deaths associated with other malignant tumors, including second primary lung cancer
, than patients who underwent lung segment resection (n=12,2%) 。 At the same time, we noticed that the proportion of patients with recurrence in the lung segment group who received thorough treatment (93%, 35/44) was higher than that in the lobectomy group (80%, 62/67), and the proportion of patients who survived after 5 years of follow-up (68% and 49%, respectively) was higher; In the treatment of second primary lung cancer, the proportion of resection in the lung segment group (89%, 32/36) was also higher than that in the lobe group (63%, 19/30).

。 Although these data do not prove that lobectomy will directly increase death except for primary lung cancer, including other malignant tumors and respiratory and cerebrovascular diseases, it can suggest that the harmfulness of lobectomy to patients with early NSCLC may be reflected in the reduced tolerance to tumor recurrence and rethetherapy of second primary lung cancer, which is different from subgroup analysis, men with lung segment resection, ≥ 70 years old, solid nodules, The overall survival of patients in the subgroup of nonadeneal cancer was significantly better than the results of lobectomy to some extent
.
Lung squamous cell carcinoma and pure lung adenocarcinoma are usually more likely to occur in elderly men, and the common feature of patients is that the cardiopulmonary function reserve is not ideal, and it is easy to combine more underlying diseases
.
Palliative lung segment resection, while often insufficient to cure primary lung cancer, helps preserve the feasibility of further treatment of respiratory, cerebrovascular, or other malignancies in advanced patients, and the JCOG0802 findings support our previous experience of preferring pulmonary segment resection from retrospective studies
.
At the same time, for patients with multiple lung cancers, segmental resection, or sub-lobectomy, is sometimes the only surgical option
.
From another perspective, for single lung cancer, especially pure solid nodules with CTR =1, if the patient is younger, has no underlying disease, or has fewer, the actual benefits of lung segment resection are debatable
.
It can be noted that the FEV 1.
0 in the 1 year after lobectomy decreased by only 12%, compared with the benefit of only 3.
5% for pulmonary segment resection, which was far from what the trial expected
.
Before finding a more appropriate lung function assessment index than FEV 1.
0 and improving the retention of lung function in sub-lobectomy, it is important to consider whether the 3.
5% benefit is worth the risk of pulmonary segment resection in the perioperative period, and whether the 3.
5% difference can be perceived by patients, and even whether certain lung segment resection can achieve actual lung function benefits
.
Nomori et al.
reported that there were no significant differences
in lung function protection and lobectomy when the range of lung segment resection ≥ 2 lung segments or ≥ 5 subsections.
Chen et al.
also pointed out that when the number of subsegments surgically removed by lung segments exceeds half of the total subsegments of the lobes, the loss of lung function is similar to the removal of the entire lobe, which means that removing less lung tissue does not necessarily preserve more lung function
.
Therefore, the first surgery to achieve the greatest possible cure of lung cancer, to avoid postoperative treatment of tumor recurrence may be more practical value
to improve the quality of life of patients.
Patients should not relax postoperative follow-up even if lobes are removed, and more aggressive treatment after recurrence will provide a definite survival benefit
.
For high-risk patient groups of stage I.
A NSCLC patients, Japanese scholars initiated a multicenter randomized controlled study, JCOG1909, in 2020 to verify the efficacy of anatomical lung segment resection compared with wedge resection
in overall survival.
Previous retrospective studies have reported that in patients who are not candidates for lobectomy, wedge resection can achieve a prognosis comparable to pulmonary segment resection and be safer and more reliable
.
Perioperative results published in the GALGB14503 study also showed that pulmonary segment resection was more likely than wedge resection to have grade 3 or higher adverse events [19% (24/129) and 11% (22/200), respectively
].
It is believed that after the data of JCOG1909 and GALGB14503 studies mature, the surgical choice of early lung cancer will be further personalized
on the basis of JCOG0802 research.

The third question is whether pure solid nodopulmonary segment resection can be used as a standard procedure
.
CTR of lung adenocarcinoma is a very key imaging indicator for prognosis
.
Long-term follow-up data from the JCOG0201 study showed that CTR=1 reliably predicted stage cT1 tumor recurrence
.
The JCOG0802 study did not provide a recurrence of a pure solid nodule with CTR=1, and it is not known
whether there has been an increase in the recurrence rate of lung segment resection.
However, according to unpublished data published by Professor Hisashi Saji, in the subgroup of pure solid tumors in the JCOG0802 study, there was no significant difference in 5-year RFS between lung segment resection and lobectomy (HR= 1.
013, 95% CI: 0.
723 to 1.
417).

Pure solid tumors have a higher probability of BEINGS-positive, and at first the risk of lung segment resection was greater, while researchers have reported that for STAS-positive stage I.
A lung segments, lung segment resection does not increase local recurrence
compared with lobectomy.
Studies have shown that for patients with STAS-positive pathological stage I.
A lung cancer, there is no statistically significant difference in RFS and total survival of lung segment resection compared with lobectomy, but there is a significant decrease
in RFS and overall survival in patients with wedge resection 。 Studies have reported that the subgroup with a limited resection margin ≥2 cm will not have a local recurrence even if there is a STAS, indicating that in the case of achieving sufficient margins, STAS does not seem to affect our implementation of lung segment resection, when we return to the question of how to improve the quality of lung segment resection, from the available evidence, we can also get inspiration from the available evidence that for high-risk nodules with ≤ 2 cm, we may need to control the distance of the incision margin of the lung segment to more than 2 cm.
Because the study of Eguchi et al.
has suggested that even if the margin distance/tumor length is ≥1, it is not enough to significantly reduce recurrence
when treating a STAS-positive nodule.

Another key factor to consider is high-risk pathological subtypes such as micropalaxis
.
Based on the proportion of different pathological components, the International Association for the Study of Lung Cancer proposed a grading system for invasive lung adenocarcinoma in 2020, and the level of grading is closely related to the proportion of solid components, and most of the Grade 3 grade (84.
7%) are pure solid nodules on CT, and are more likely to have KRAS mutations
with a higher degree of malignancy.
However, there is a lack of efficacy for
different surgical procedures in high-grade lung adenocarcinoma.
Previous studies have shown that micropachinal components account for ≥5% of patients with subpulmonary lobectomy as an independent risk factor for postoperative recurrence, but not as a risk factor
for recurrence in patients with lobectomy.
Researchers have further pointed out that when the micro-papillary component >5%, the RFS and overall survival of lung segment resection are significantly inferior to lobectomy
.
How to screen patients who are not suitable for lung segment resection from pure solid tumors with CTR=1 is a question that the JCOG0802 study cannot answer, so from the perspective of malignant tumor control, pulmonary segment resection should be performed with extreme caution
。 Starting from the subgroup analysis of the JCOG0802 study, for tumors with CTR=1, the RFS of lung segment resection was not inferior and achieved a very significant improvement in overall survival, whether this improvement was related to the primary lung cancer itself, this study may suggest that for high-risk pure solid nodules, the effect of lobectomy may not be ideal, and adjuvant chemotherapy or targeted therapy is needed to further improve efficacy
.

V.
Implications of the JCOG series of studies

Histopathology is the gold standard for definitive diagnosis, evaluation of prognosis, and guidance of treatment for any tumor, including lung adenocarcinoma
.
In the new classification of lung adenocarcinoma introduced by the WHO Lung Cancer Classification System, it provides a possible pathological reference for GGO with different lengths and different solid component sizes in CT tomography images, reflecting the important value
of imaging performance in assessing the benign, malignant and prognostic outcome of GGO-type lung adenocarcinoma 。 In the JCOG0201 study, the imaging manifestations of tumor length ≤ 2 cm, CTR≤ 0.
25 predicted that the specificity of pathology as non-invasive lung adenocarcinoma could reach 97.
5%, and the results of the JCOG0804 study showed that direct wedge resection or lung segment resection can achieve radical cure
。 Also based on another set of imaging features identified in the JCOG0201 study, the results of the JCOG1211 study showed that the prognosis of adenocarcinoma with a tumor length ≤3 cm and a CTR≤ of 0.
5 was also excellent
for lung segment resection and dissection of hilar lymph nodes 。 It can be said that for the surgical treatment of GGO-based peripheral early-stage lung adenocarcinoma, the prospectively designed JCOG series of studies fully answered two key questions, standardized limited resection or sub-lobectomy can achieve equivalent or even better overall survival than standard lobectomy without increasing local recurrence and can directly determine the operation through imaging performance, without having to perform a small sample biopsy before surgery or determine the surgical strategy through the results of frozen pathology during surgery
。

CTR itself is not a perfect indicator, just as the density of ground glass in imaging does not always correspond to the adherent growth component of lung adenocarcinoma in histopathology, and the solid high density does not necessarily reflect infiltrating the growing adenocarcinoma tissue
.
In the case of uneven density within GGO or multiple solid stoves, we can only roughly measure the largest solid component, but in theory, all solid stoves should be taken into account; To complicate matters further, if there is a high density of the sieve distribution, it is possible that the actual proportion of the solid components is very small but the measured CTR is almost 1
.
CTR=0.
5 is not strictly speaking the dividing line between GGO-dominant and solid component-based partial solid nodules, let alone pathologically AIS or MIA and invasive adenocarcinoma
.
Imaging indicators may be more prognostic than CTR in the future, and the presence of GMOs may itself be an indication for sub-lobectomy, regardless of the number of
CTR.
The significance of the CTR or the JCOG series of studies is that in clinical practice, the decision on how much to cut is directly left to the surgeon, and the scope of surgery does not need to be determined based on the ambiguous intraoperative frozen pathological results in many cases, even if our measurement of CTR is sometimes not accurate
.
Moreover, there is no need for more scruples when performing sub-lobectomy, whether it is wedge resection or lung segment resection, as long as the surgical standards for lung cancer are strictly adhered to, the entire lobe should not be removed from the perspective of overall survival benefit, which helps physicians who are not yet proficient in lung segment resection to further refine surgical techniques
.

Since the use of CTR>0.
5 criteria includes some lung cancer patients with extremely heterogeneous tumor biology, including more than 50% of pure solid tumors, the JCOG0802 study is currently the most complex and informative study
in the series 。 No study is absolutely perfect, and the JCOG0802 study also leaves many unanswered questions, such as the intrinsic link between the increase in local recurrence in the lung segment group and the increase in the number of non-lung cancer deaths in the lobe group and the choice of surgical method, and our inability to further screen out high-risk lung cancers to avoid unreasonable lung segment resection
.
In the head-on contest between lung segment resection and standard lobectomy, the positions are different, and the results of the interpretation will naturally be quite different
.
Segment resection was inferior to lobectomy in local control of the tumor, and overall survival of pulmonary segmentectomy was still better than standard lobectomy in subgroup analysis of solid nodules
.
The specific embodiment of these differences is that some patients are not completely removed and need to be re-operated to make up for it, while some patients have too many resections and bear more risks
from other diseases.
What we need to always keep in mind is that the fundamental purpose of conducting such a large-scale multicenter randomized controlled study is to guide real-world clinical practice, and the interpretation of the results needs to be substituted into real clinical scenarios
.
How real-world thoracic surgeons choose a truly individualized surgical protocol for a patient from the perspective of patient benefit and complete the procedure with high quality is more meaningful
than figuring out which surgical procedure can be called standard treatment under what circumstances.

The completion of protocol-compliant surgical quality control at 70 thoracic surgery centers and the long-term follow-up of thousands of patients is a difficult task, so the JCOG0802 study has a very high internal authenticity
.
However, different medical centers and different practitioners necessarily have differences in the quality and speed of surgical completion, which makes the external authenticity of the JCOG0802 study not necessarily equally impressive
。 In the real world, in centers with a high proportion of lung segment resection, the time required to complete lung segment resection is almost no different from that of lobectomy, and even complex lung segment resection is no different from that of dominant lung segment resection; In medical centers where pulmonary segment resection is performed at a low rate, as reflected in the perioperative results of the JCOG0802 study, pulmonary segment resection takes more time and can have more complications
.
Some physicians use 3D-CTBA to guide lung segment resection, which can be done well and quickly; Some physicians still perform lung segment resection based solely on tomographic CT imaging, which is bound to increase the risk of local recurrence after surgery
.

The surgical techniques of lung cancer surgery are constantly evolving, and the evaluation of surgical methods is essentially an evaluation
of the degree of completion of the surgeon's surgery.
During the enrollment of the JCOG0802 study, there were still large sample studies reporting that lobectomy was significantly better than lung segment resection for 5 years of survival and malignant tumor specific survival in patients with stage I lung cancer, which obviously did not fully reflect the true level
of lung segment resection at that time 。 After the JCOG0802 study, pulmonary segment resection has undergone 10 years of development, and many medical centers in China are routinely carrying out anatomical partial lobectomy or sub-lobectomy based on preoperative three-dimensional reconstruction, which is no longer limited to the joint resection of single lung segment or double lung segment in that period, and the concept and quality of localized lung resection have been further improved
.
From an evidence-based medical perspective, the JCOG0802 study provides limited but highest-quality evidence
that pulmonary segment resection becomes the standard surgical modality for small-sized (≤2 cm) peripheral NSCLC.
At the current level of actual development of lobectomy, precise lung segment resection planned using three-dimensional reconstruction should be an essential skill
for every lung cancer surgeon.
Precision lung segment resection helps us manage multiple lung nodules at the same time and reserves the possibility
of further treatment for possible secondary primary cancer, respiratory disease, or cerebrovascular disease.
Screening patients with pathological risk factors for postoperative adjuvant therapy and aggressive treatment of recurrent tumors can maximize survival
.

Starting from the actual clinical application scenarios, the JCOG Lung Cancer Surgery Series simplifies the problem of the best surgical treatment methods for early lung cancer, and opens up a new path
for determining surgical strategies through preoperative imaging performance.
Including the JCOG1906 and JCOG1909 studies, Japanese scholars are also preparing to repeat the 0802 study (JCOG21XX) in patients with tumor lengths of 2 to 3 cm and CTR ≥ 0.
5, and it is expected that these well-designed imaging guidance studies can provide more insights
for the surgical treatment of early lung cancer.

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