Radiotherapy for non-small cell lung cancer
I. Non-small cell lung cancer with medical disease that is inappropriate for surgery or in which the patient is unwilling to undergo surgical management.
External radiotherapy is more suitable for non-small cell lung cancer patients who are not suitable for surgery or unwilling to receive surgical treatment, but the survival is not as good as surgical resection, which may be due to the difference in patient selection, because some patients transferred from surgery to radiotherapy department have poor general condition, especially poor lung function, and are prone to complication of radiation pneumonia; moreover, there is a difference in staging after surgery and before surgery, and 25% to 50% of lung cancer patients who are stage I before surgery have increased staging. ～In addition, the stage of lung cancer is different from that before surgery.
For radiotherapy of stage I and II non-small cell lung cancer patients, the main issue is how much radiotherapy dose should be given, that is, the relationship between the amount of radiotherapy and the size of the tumor, local control rate and survival rate. For primary foci in the lung smaller than 3M, the radical radiotherapy dose generally needs 65 Gy; for larger tumors, it is difficult to achieve complete remission with such a dose, so the amount of radiotherapy for lung cancer should depend on the size and stage of the tumor.
Most scholars do not advocate mediastinal lymph node radiation for early-stage lung cancer, especially for peripheral type lung cancer. Therefore, if there is no metastasis in the mediastinal lymph nodes, only the primary foci can be treated with radiotherapy. It has been reported that only 10% of lung cancer patients who do not irradiate mediastinal lymph nodes will develop mediastinal lymph node metastasis in early stage lung cancer, which leads to treatment failure; it has been reported that even if 40 Gy of preventive radiotherapy is given to mediastinal lymph nodes, 10% of patients still develop mediastinal lymph node metastasis after radiotherapy, which indicates that 40 Gy of radiotherapy to mediastinal lymph nodes is not enough.
Radiotherapy for locally advanced lung cancer
For locally advanced lung cancer that cannot be removed surgically, radiotherapy is one of the important treatment means, but the survival rate of radiotherapy alone is low, and chemotherapy or radiotherapy followed by surgery is the best treatment method.
Radiotherapy alone: The American Radiotherapy Treatment Collaborative Group (RTOG) studied 376 patients with locally advanced lung cancer who received different radiation doses 30 years ago, with 40, 50 and 60 Gy radiation therapy doses, the median survival period was 9 months, the 5-year survival rate was 5%, and the short-term survival rate was better with 60 Gy. The local recurrence rate was 53%-58% in the 40 Gy group and 35% in the 60 Gy group.
Sequential radiotherapy versus radiotherapy alone: Since patients with locally advanced non-small cell lung cancer often develop distant metastases after radiotherapy leading to treatment failure, sequential combination of radiotherapy and chemotherapy has the advantage of mutual compensation. Previous clinical trials using sequential radiotherapy did not yield positive results because of the absence of platinum-based chemotherapeutic agents and the poor general condition of the patients. Later, platinum-containing (DDP 100 mg/O x 2, vincristine 5 mg/O) combined with 60 Gy of local radiotherapy was chosen, and patients with a cassette score of >80, weight loss of up to 5% and hemoglobin pressure of >30% had a median survival of 14 months in the sequential radiotherapy group (n=78) versus 10 months in the radiotherapy-only group (n=77) (p=0.006). The three-year survival rates were 23% versus 11%, respectively.
Simultaneous radiotherapy versus radiotherapy alone: EORTC reported that daily radiotherapy with DDP 6 mg/O combined with 55 Gy was more effective than weekly radiotherapy with 30 mg/ODDP combined with radiotherapy or radiotherapy alone, with 3-year survival rates of 16%, 13% and 2%, respectively.
Sequential chemotherapy + radiotherapy versus concurrent radiotherapy: Four clinical trials have reported comparing the clinical outcomes of sequential chemotherapy + radiotherapy versus concurrent radiotherapy. The 5-year survival rate increased from 9% to 16% with MVP induction chemotherapy combined with 56Gy radiotherapy versus the same regimen of concurrent radiotherapy, but also increased with radiation esophagitis.
RTOG comparison: 1) DDP/vincristine + radiotherapy 60Gy sequential , 2) simultaneous DDP/vincristine + radiotherapy 60Gy, 3) simultaneous DDP/with oral VP16 + hyper-segmented radiotherapy 69.6Gy. final analysis yielded a longer median survival with simultaneous radiotherapy (14.6 Vs 17.1 months).
Sequence of radiotherapy: there are three sequences of chemotherapy with carboplatin + Tysodi combined with 66Gy radiotherapy. The first is chemotherapy followed by radiotherapy; the second is induction chemotherapy followed by radiotherapy synchronization; and the third is synchronized radiotherapy followed by consolidation chemotherapy. Synchronized radiotherapy was significantly higher in those who developed esophagitis, with a median survival of 11 and 12.5 months for the first and second treatments, respectively, while the third method had a median survival of 16.5 months.
Consolidation chemotherapy: SWOG9019 reported a three-year survival rate of 17% for patients with stage III non-small cell lung cancer treated with DDP/VP16 consolidation chemotherapy at the end of concurrent radiotherapy and SWOG9504 reported a three-year survival rate of 37% with Tysodi consolidation chemotherapy. Consolidation chemotherapy deserves further study.
III. Unconventional fractionated radiotherapy
Fractionated radiotherapy: radiotherapy is divided into several stages, usually 2-4 weeks between radiotherapy, so that patients can recover. However, RTOG73-01 proved that the local control rate of 40Gy fractionated radiotherapy is worse than that of continuous 40Gy radiotherapy. Therefore, the segmented (2-3 week interval) radiotherapy regimen is not used nowadays.
Hyper-segmented radiotherapy.
The radiotherapy regimen of 1.2Gy twice a day is hyper-segmented radiotherapy, which has an increased radiotherapy dose compared with conventional radiotherapy (2.0Gy once a day). Theoretically, the killing of tumor cells is also increased, and the side effects on normal tissues (slow-responding tissues) are not increased.
In the phase I/II clinical trial, Cox treated locally advanced non-small cell lung cancer with 69.6 Gy using hyperfractionated radiotherapy and had a median survival of 13 months, but the phase III clinical trial did not show any benefit.
Accelerated hyperfractionated radiotherapy: 1.5 Gy three times a day for 12 days for a total of 54 Gy. The theory of accelerated hyperfractionation is that tumor cells undergoing radiotherapy will accelerate the re-proliferation rate.
Phase II clinical trial showed 100% radiation esophagitis, 10% radiation pneumonia, and 34% 2-year survival rate.
Phase III clinical trial: 13 units in the UK jointly conducted a phase III clinical trial, and the 5-year survival rate was 29% with accelerated hyperfractionated radiotherapy compared to 20% with conventional 60 Gy radiotherapy. However, the rate of severe radiation esophagitis also increased from 3% to 19% with conventional fractionated radiotherapy, and the rate of radiographic fibrosis after 2 years was 4% with conventional fractionated radiotherapy compared to 16% with accelerated hyperfractionated radiotherapy.
Accelerated hyperfractionated radiotherapy increases the workload of the radiotherapy department and requires hospitalization, which increases the medical costs of patients.
Conformal radiotherapy
By linking CT with radiotherapy planning system, the images are reconstructed to find out the extent of tumor and radiation treatment with multiple incidence angles. The results of the RTOG9311 research project show that if 37% of the lung tissue is irradiated with no more than 20 Gy, the safe dose of conformal radiotherapy reaches 77.4 Gy. If 25% of the lung tissue is irradiated with no more than 20 Gy, the maximum tumor volume can reach 90.3 Gy.
Target area determination
The standard target area should include visible primary and subclinical foci, such as lymph nodes to be included in the radiation field, ipsilateral hilum, whole mediastinal lymph nodes and supraclavicular lymph nodes can be considered. The radiation margins are expanded by 1 to 2M due to lung tissue movement with respiration and positioning errors with each radiotherapy session. For subclinical foci, if no metastasis is seen in the lymphatic drainage area as described above, radiotherapy of 40 Gy is sufficient, followed by radiotherapy for clinical foci. Increasing the radiotherapy lymphatic drainage area will increase the complications of lung radiotherapy, therefore, some centers do not prevent irradiation of lymphatic drainage area. SKCC reports selective radiotherapy of lymph nodes with 8% lymph node recurrence rate and 65% regional recurrence rate, which indicates that the known lesions (clinical foci) are well controlled before considering mediastinal and supraclavicular lymph node radiotherapy.
IV. Application of PET
PET has become a reference for radiation treatment planning, and Mah reported that three experienced radiologists were asked to outline 30 lung cancer radiotherapy lesions with reference to CT or fusion of CT and PET. With PET reference, there were 7 out of 30 patients.