The first show of Guangdong Congress (Part 1): True and false CR after ALK-positive lung adenocarcinoma targeted therapy

Cases diagnosed at this MDT conference 1.
Case introduction The patient is a 32-year-old male, who has smoked for 8 years, has quit smoking for 6 years, has no family history of tumors, and has a PS score of 1 point.

The patient had a physical examination on 2019-02-22, chest CT showed: a solid nodule in the posterior segment of the right upper lobe, 8×7mm, it is recommended to review it after 2 months; 2019-04-07 re-examination of the chest CT: a solid nodule in the right upper lobe Section, 8×7mm, no significant change from the previous; 2019-11-29 CT review of chest CT showed: new right hilar solid nodule 14×12mm, new multiple subpleural solid nodule, original 8mm nodule There is no change from the previous.

2020-2-11 CT review showed that the maximum diameter of the right hilar nodules increased to 18mm, and the remaining lung nodules increased to varying degrees.

2020-04-26 PET: The maximum diameter of the right hilar nodules increased to 33mm, multiple subpleural nodules increased, and glucose metabolism increased.
Consider the right upper lung malignant tumor, with right upper lung and multiple pleural metastases.

2020-5-06 Pathological biopsy of pleural nodules revealed invasive adenocarcinoma, some of which were mucinous adenocarcinoma.

1.
Immunohistochemical markers: tumor cells CKpan(3+), CK7(3+), TTF-1(3+), NapsinA(3+), P63(-), CK20(-), Villin(-), CDx-2 (-), CDH17 (-), SATB2 (-), Ki67 (about 30%).

2.
VENTANA immunohistochemical markers: tumor cells ALK-EML4 (+), ALK-neg (-).Diagnosis: right upper lung adenocarcinoma cT3satN0M1a (pleura) stage IVa; 2020-5-20 start aletinib 600mg bid treatment; 2020-06-15 CT: multiple solid nodules in the upper right lobe are earlier (04-26) The small solid nodules under the pleura disappeared partially, and the efficacy was evaluated as PR; after the treatment, sinus bradycardia occurred, and the dose of aletinib was reduced to 450 mg bid; the chest CT was regularly rechecked, and the nodules were unchanged.

2021-03-10 PET/CT showed that the right upper lobe lesion was a 6mm cord-like tissue, and the hilar lesion was a 6mm cord-like tissue.
There were no pleural nodules, and there was no increase in metabolism in each nodule.

★Diagnosis and treatment timeline 2.
Discussion points 1.
Can the image CR be evaluated at present; 2.
Formulate the next treatment plan.

3.
Department opinion The patient was diagnosed with right upper lung adenocarcinoma cT3satN0M1a (pleura) stage IVa ALK-EML4(+), and the curative effect of aletinib was evaluated as PR, close to CR; and he was a young male with good lung function.

Opinions of the department: 1.
Resection of the tumor bed of the original primary lesion (upper right lung apex + posterior segment resection) + pleural biopsy (suspected under microscope); 2.
Continue aletinib treatment after surgery; 3.
ctDNA dynamic monitoring of MRD, regular follow-up Chest CT, head MRI.

4.
Expert speech ▷Zhou Qing (host of the General Assembly Clinic and chief physician of the Third Pulmonary Department of Guangdong Provincial People's Hospital): First of all, from the perspective of imaging analysis, there is only a cord-like shadow at present, and the PET examination does not increase the metabolism.
Can it be evaluated? RECIST CR? ▷ Liu Hui (Chief Physician, Department of Radiotherapy, Sun Yat-sen University Cancer Center): For this case, the focus of the patient was significantly reduced or even disappeared after targeted therapy, which was very close to CR.

The existing streaks are likely to be residual fibrous scars after the tumor disappears and cannot be completely absorbed.
Therefore, the residual streaks in the lungs do not mean that the patient has residual tumors.

▷Zhong Xiaomei (Deputy Chief Physician, Department of Radiology, Guangdong Provincial People’s Hospital): The patient’s current primary lung lesions and hilar lesions still have stripe-shaped shadows, which have not completely disappeared.
The evaluation is that CR needs to be cautious, and the individual is more inclined to evaluate it as The standard for CR imaging evaluation of PR is to completely disappear the lesion, but whether there is residual tumor needs to be confirmed by pathology.When using PET for examination, the tumor needs to have a certain size to show high uptake activity.
The remaining lesions in this patient are already small and may not be able to show high metabolic levels, and special types of tumors can show low metabolism or even no metabolism.
Metabolism, for this patient, it is necessary to be cautious to evaluate whether to achieve CR from whether PET has metabolism.

▷Yan Lixu (Deputy Chief Physician, Department of Pathology, Guangdong Provincial People’s Hospital): Because after targeted therapy kills tumor cells, the remaining lesions only have a small amount of tumor cells and fibrous scars.
In this case, the lesions are displayed on PET The uptake activity is not high and it is difficult to observe.

Judging from tumor specimens operated on after neoadjuvant targeted therapy, most of the original tumor beds still have a small amount of tumor cells remaining, and targeted therapy is usually difficult to achieve pCR.

RECIST CR is not the same as pathological CR.

▷Zhou Qing (host): The patient's targeted therapy has achieved the best curative effect at present, the imaging is close to CR, and PET also shows low metabolic activity.
Is it necessary to receive local treatment in this case? Experts in internal medicine, surgery and radiotherapy are invited to express their opinions.

▷ Feng Weineng (Chief Physician of Tumor Center, Foshan First People's Hospital): From the perspective of internal medicine, patients receive targeted therapy with good results.

Although the lesions on PET have disappeared, we still need to use thoracoscopy to explore whether the patient currently has pleural metastasis.

If there is no pleural metastasis, the value of local treatment is greater.
If there are still pleural metastases, the value of local treatment will decrease a lot; whether radiotherapy or surgical resection is used requires the radiotherapy department and surgeon to give treatment advice.

▷Zheng Yanfang (Chief Physician, Guangzhou Medical University Cancer Hospital): The patient is 32 years old, has good lung function, and is well tolerant of surgery.

I advocate surgical treatment, remove the primary lesion as much as possible, and continue targeted therapy to maintain it, so that the patient's survival benefit will be the greatest.

If it is an elderly patient, I suggest only taking aletinib treatment.

▷Pan Yi (Chief Physician, Department of Radiotherapy, Guangdong Provincial People's Hospital): This case has several characteristics: 1.
The number of lesions increased significantly within 9 months from the discovery of the lesions, indicating rapid progress without treatment; 2 From the imaging point of view, it is a patient with low residual; 2.
Aletinib has a good treatment effect, and the efficacy evaluation PR is close to CR; currently for patients with stage IV residual, whether it is from a prospective study or a retrospective study See, there is a survival benefit with local treatment.

As for radiotherapy or surgery, the two methods have their own advantages and disadvantages.
The surgical trauma is more traumatic but pathological specimens of the tumor can be obtained.
However, in this case, the location of the lesion with few residual lesions is deeper, and the operation may require segmental resection of the lung.
Therefore, I recommend radiotherapy .

▷ Liu Hui: For follow-up treatment, I consider two questions.

1.
The patient had multiple pleural nodules before, and our local treatment may eventually fail because of this.
This requires communication with the patient and his family before treatment; 2.
The patient has residual cord-like lesions and cannot be determined whether CR.

However, considering the gradual increase in the dose of radiotherapy, it is still a question whether a sufficient dose can be achieved in a lesion less than 1 cm.

Compared with radiotherapy, surgery can be removed cleanly, and the pathological specimens obtained can guide follow-up treatment, and patients can also tolerate surgery.

In summary, I think surgery is better for patients.

▷Yang Xuening (Chief physician of the Department of Pulmonary Surgery, Guangdong Provincial People's Hospital): The patient's current curative effect is evaluated as clinical CR.

Request for MRD detection to monitor tumor burden during the consultation.

However, the MRD was not tested before the operation, and it can be considered to supplement the MRD test in the current state of the patient; if the MRD is positive, then the operation may be of little significance.

In addition, the study of advanced lung cancer oligometastasis local consolidation therapy study did not include pleural metastases.
Therefore, there is insufficient evidence of local treatment benefits for patients with multiple pleural metastases, so I do not recommend surgical treatment.

▷Zhong Wenzhao (Chief physician of the Department of Pulmonary Surgery, Guangdong Provincial People's Hospital): This patient is a stage IV ALK-positive lung adenocarcinoma, and achieved clinical CR after treatment with aletinib; the current controversial issue is whether to take further local treatment.

A number of phase II clinical trials have confirmed that local treatment for patients with stage IV oligometastatic lung cancer can benefit both PFS and OS; the most famous one is the study from MD Anderson.
The PFS of the local treatment group vs.
the control group is 14.
2 Compared with 4.
4 months, OS is 41.
2 months vs 17 months1,2.

In terms of tumor evolution, this case is unique in that it is parallel and non-linear evolution.
In addition, it includes multiple pleural metastases near the diaphragm (14 places?), which is difficult to remove by surgery.

Therefore, the benefit of surgery is limited.

▷Wu Yilong (Professor of Oncology, Guangdong Provincial People's Hospital): This case is very unique, and we can learn a lot from it.

First, we need to grasp three key issues.

First, on the basis of the good curative effect of systemic treatment, do patients in stage IV need to add local treatment? When judging whether to add local treatment, we first recommend a PET-CT examination to better judge the general condition.

If patients can achieve CR after systemic treatment, they will have the greatest survival benefit.

After systemic treatment, if there are still isolated residual lesions, adding local treatment at this time can help achieve CR.

Second, what is the timing of adding local treatment? There are currently two main ways.

1.
Actively add local treatment when the effect is the best.

2.
When it is found that the lesion is slowly increasing, passively add local treatment.

For targeted therapy, the curative effect will reach a plateau after three months of taking the drug.
At this time, the timing of local treatment should be grasped.

Thirdly, what kind of local treatment is adopted? We need to judge according to the principle of least trauma.

When we return to this case with the above-mentioned thinking perspective, the patient still has residual fibrous lesions in current imaging, combined with previous clinical trial data, and further proactively adding local treatment, it is expected to further help the patient achieve CR and prolong the remission time; current PET/ CT showed that the pleural lesions disappeared.
The surgical difficulty should not be too difficult to remove the remaining fibrous lesions.
Further surgical resection of the tumor bed may be considered, and the targeted therapy of aletinib will continue to be maintained after the operation.

▷Zhou Qing (host): For stage IV lung cancer that is all well-controlled by treatment, the effect of local treatment to promote patients to achieve clinical CR can help prolong the PFS and even OS of the patients.

The timing and method of local treatment are two major elements that clinicians need to consider, and the principle of minimal trauma is generally adopted.

Through multidisciplinary consultation, the pros and cons of various treatments can be comprehensively evaluated, and the best plan can be given to the patient.

The patient’s final consultation opinion is for surgical treatment, and we will continue to follow up the follow-up pathological results.

V.
Summary of MDT This patient is a right lung adenocarcinoma cT3N0M1a stage IVa ALK-EML4 (+), treated with aletinib, with residual fibroid lesions in the upper right lung, and the curative effect of pleural lesions is close to CR.

The main opinions of the MDT discussion are as follows: 1.
The case cannot be considered to achieve imaging CR, 2.
It is recommended to add local treatment, surgical resection is the first choice, and 3.
Postoperative aletinib maintenance treatment.

Sixth, the editor observes the value of local treatment for oligo-lesions after systemic treatment of stage IV NSCLC has been recognized by everyone, but the treatment method is still worth discussing.

An interesting phenomenon emerged during the discussion of this case.
Surgeons did not advocate surgery.
On the contrary, experts in internal medicine and radiotherapy supported surgery.

I think the possible reason is that the two planned resection lesions are not peripheral.

Therefore, even if only the lung segment is made, it is not a simple lung segment, let alone after treatment with ALK inhibitors.

Also consider the possibility of pCR cut out, and the uncertainty of the treatment of pleural disseminated cases with few residues.

But after all, surgery is the only way to reveal whether the pCR is reached.

We will wait and see what the follow-up pathological outcome will be.

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TheLancet Oncology 2016; 17(12):1672-82.
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Source: Reprinted from " CTONG"