Advanced Stage III-IV Non-small Cell Lung Cancer
Background
Approximately 30% of all NSCLC have locally advanced disease, Stage IIIA at presentation. Stage IIIA disease is considered to be hilar adenopathy and large tumors or tumors that invade the chest wall or disease with nodes that do not cross the midline. (T1-3 N2, T3N1-2, T4 N0-1.
25% will be seen to have occult N2 (ipsilateral mediastinal or subcarinal) disease at initial surgery.
Frequently metachronous primarys will occur. By defnition, after definitive treatment of a primary lung cancer, a second primary is considered any disease that develops at ≥ 2 years after completion of that treatment. Whenever a recurrence with identical histology appears at < 2 years this is considered a metastasis.
Brain involvement is frequent with 15% - 30% of all NSCLC patients developing brain metastases. PCI has been tried with no real success. Unlike small cell lung cancer, PCI has not demonstrated an increase in median survival or a decrease in CNS incidence, as it is likely there is reseeding from a primary disease.
Pancoast Syndrome is the result of a superior sulcus tumor (apex) invading the thoracic inlet and compressing by mass effect the structures. These structures include:
- Sympathetic ganglion
- brachial plexus
- recurrent laryngeal nerves
- vasculature compromise causing arm and shoulder pain
- Horner syndrome
- hoarseness
- parasthesias of the ulnar distribution
- SVC syndrome
Horner's Syndrome results from tumor compression of the sympathetic ganglion which causes ipsilateral miosis (contraction of pupil), partial ptosis (droopy eyelid), and anhidrosis,
Superior sulcus tumors account for about 3% of all NSCLC.
T | N0 | N1 | N2 | N3 | M1 |
T1 | IA | IIA | IIIA | IIIB | IV |
T2a | IB | IIA | IIIA | IIIB | IV |
T2b | IIA | IIB | IIIA | IIIB | IV |
T3 | IIB | IIIA | IIIA | IIIB | IV |
T4 | IIIA | IIIA | IIIB | IIIB | IV |
Workup and Staging
Staging
Advanced NSCLC is defined as Stage IIIA/B and Stage IV. The TNM components that are incorporated are:
Stage IIIA: | T3N1, T1-3N2 |
Stage IIIB: | T1-3N3, T4N0-3 |
Stage IV: | T1-4N003M1 |
M1a was introduced in the 2009 IALSG and AJCC staging to incorporate the case of a malignant pleural effusion. Median survival of those who are staged M1a (malignant effusion) is between 3 and 0 months.
PET/CT may improve the staging workup to spare patients from futile thoracotomies because of the discovery of unresectable disease prior to the operation, which cannot be detected by CT. A Danish RCT (Fischer 2009 NEJM) examined CT + mediastinoscopy or PET/CT staging. This study randomized 189 patients to preoperative CT + mediastinoscopy or PET/CT. PET/CT reduced the number of futile thoracotomies from 38 to 21 and the overall number of thoracotomies to 60 from 73. These results are statistically significant. The overall mortality did not differ between the groups.
Treatment and Prognosis
The general treatment options for locally advanced Stage IIIA disease (cN2) is:
- Definitive Chemotherapy with concurrent radiation therapy
- Neoadjuvant Chemo-radiation therapy → lobectomy per INT-0139
- Induction chemotherapy alone → surgery
25% of NSCLC have occult N2 disease only seen at thoracotomy. In this situation, the recommended procedure is to continue to dissect if technically feasible with only an occult single station mediastinal node. Surgical resection should proceed with lung resection and mediastinal ned dissection followed by adjuvant chemotherapy and consideration of PORT.
Surgery
Surgery is usually not feasible as initial treatment in locally advanced lung cancer, due to bulky, unresectable disease. Bulky, unresectable disease is considered to be a histologically confirmed lymph node > 2 cm on CT, extracapsular extension, or multistation nodal disease, regardless of size.
For patients with satellite nodules in the same lobe, T3 disease, OS-5 is 33% if these patients undergo lobectomy. Careful nodal assessment must be performed to exclude N2 disease.
Chemotherapy
Preoperative/Induction Chemotherapy
Clinical trials exist demonstrating a survival benefit of adding pre-operative induction chemotherapy for IIIA-B NSCLC. Three trials have demonstrated this and the NCCN 3.2011 guidelines also recommend pre-operative chemotherapy ± RT.
MDACC (Roth, 1994 JNCI, 1998, Lung Cancer) randomized 60 patients to surgery or chemoptherapy (CDDP/VP16/cyclophosphamide) for one cycle → surgery. Median survival improved from 14 months to 21 months with pre-op chemotherapy
Madrid Data (Rosell 1994 NEJM) randomized 60 patients to surgery or CDDP/Isfosfamide/mitomycin-C for 3 cycles → surgery. Median survival improved to 22 months in the chemotherapy arm compared with 10 months for surgery alone.
Spanish Lung Cancer Group Trial 9901 (Garrido 2007 JCO) Phase II Study enrolled 136 patients with Stage IIIA (N2) or State IIIB (T4N0-1) to CDDP/gemcitabine/docetaxel for three cycles → surgery. There was a pCR in 13%, Median survival was 48.5 months for R0 resections, and 19.2 months for R1-R2 resections. The overall complete (R0) resection rate was 69%. Median survival was 16 months and OS-3 was 37% and OS-5 was 21%.
JCOG 9209 (Nagai, J Thorac Cardiovasc Surg, 2003) demonstrated no benefit to induction chemotherapy. This was a Japanese trial that closed early due to poor accrual in 2003 which enrolled 62 patient with IIIA N2 disease randomized to surgery alone or induction CDDP/vindestine x 3 cycles → surgery. They reported no difference in median survival at 16 - 17 months and no difference in OS-5 at 10% with chemotherapy compared with 22% with surgery.
Postoperative adjuvant chemotherapy
The LACE meta-analysis by Pignon (2008 JCO) of 5 adjuvant chemotherapy trials demonstrated a OS-5 survival advantage of 5% with post-operative chemotherapy in Stage II-IIIA patients.
CALGB 9633 (Strauss 2008 JCO) demonstrated a trend toward survival benefit with adjuvant chemotherapy for tumors > 4 cm.
There is not conclusive data demonstrating the need to add radiation therapy to chemotherapy in completely resected Stage IIIS N2 NSCLC. The CALGB 9734 Study (Perry 2007 Lung Ca) attempted to answer the question of adjuvant chemotherapy alone compared with chemotherapy → RT but was unable to accrue patients and closed due to poor accrual. There was no difference in DFS or OS. Based on a retrospective analysis, patients with N2 disease should be evaluated for chemotherapy → PORT.
Consolidation Chemotherapy after CRT
There is an uncertain role for consolidation chemotherapy. SWOG 9504 Phase II Trial showed improved median survival with consolidation docetaxel in Stage IIIB disease after definitive CRT, but the Hanna Trial, a randomized Phase III Study (Hanna, 2008 JCO) demonstrated no benefit and increased toxicity and treatment related deaths with consolidation chemotherapy. There may be a role for other agents, such as pemetrexed as maintenance therapy.
Radiation Therapy
Dose and Volume
MSKCC Dose and volume techniques for locally advanced NSCLC are as follows:
- GTV = PET positive areas, biopsy proven lymph nodes, lymph nodes > 1.5 cm on CT
- PTV = GTV + 1 - 1.5 cm
- 3D-CRT or IMRT technique to 63 - 66 Gy or higher at 1.8 - 2.0 gy/fraction should be delivered.
There is no role for radiation in malignant pleural effusions (Stage M1a). These should be treated mechanically with pleurodesis or chemotherapy. Radiation can only make things worse.
RTOG 7301 (Carlos 1980 Cancer) established a minimum dose fo 60 Gy for definitive radiation therapy treatments. Perez enrolled Stage IIIA/B patients in this dose escalation study of radiation therapy alone to 40 Gy, 50 Gy , and 60 Gy compared with 40 Gy split course at 2 Gy/fraction. Local control improved with 60 Gy and 60 Gy was established as standard. Median survival was 10 montsh and OS-3 was < 10% for all arms.
For pre-operative radiation therapy dose should be limited to 45 Gy. If dose exceeds 50 Gy bronchopleural fistual, prolonged air leak with empyema and prolong post-operative ventilation complications are seen.
Altered fractionation schemes in several Phase II-III trials have demonstrated a benefit.
RTOG 8311 (Cox 1990 JCO) Phase I/II Trial of unresectable N2 disease treated BID This trial studied 828 patients with unresectable N2 disease treated at 1.2 Gy BID to 50, 64.8, 69.6, 74.4 and 79.2 Gy. Favorable patients did better and favorable patients with good performance status that received > 69.6 Gy had significantly better OS-3 at 20%
CHARTPhase III Study (Saunders 1997 Lancet) studied 563 patients randomized to 54 Gy @ 1.5 Gy TID for 12 days or 60 Gy for 6 weeks. There was a 10% improvement in absolute survival at 3 years for CHART compared to standard fractionation. Results were similar if chemotherapy was added. Esophageal toxicity was the most common side effect at 19% compared with 3%.
ECOG 2597 (Belani 2005 JCO) examined 141 patients with Stage IIIA/B unresectable NSCLC treated with induction carboplatin/taxol for 2 cycles → definitive RT. RT Dosing randomization arms:
- Daily radiation to 64 Gy
- HART 1.5 Gy TID x 2.5 weeks to 57.6 Gy
This study closed early due to poor accrual. There was a trend toward better survival with HART with median survival 20.3 months improved from conventional fractionation of 14.9 months. There was increased esophagitis in the HART arm.
Elective Nodal Radiation
"If you can't cure what you see, then how can you cure what you can't see." A. Turrisi. There is no role for elective nodal radiation. The current recommendations are to treat with CRT only the involved fields as determined by imaging or pathology to improve the ability to increase the dose escalation.
MSKCC (Rosenzweig 2007 JCO) retrospectively reviewed 524 MSKCC patients treated with 66 Gy using 3D-Conformal RT to areas of gross disease. He found the total elective nodal failures were 6.1%. The 2 year primary tumor (in field) control rate was 51%. The elective nodal failure rate at 2 years was 7.6% and patients with local disease control had a 9% failure rate.
Yuan's Prospective Phase III trial (2007 ASCO) of inoperable Stage III disease randomized to involved field or elective nodal RT. IFRT acheived better overall response and improved LC-5 of 51% compared with 36%.
Induction Chemotherapy prior to surgery
SWOG 8805 Phase II study of Stage IIIA/B patients receiving induction chemotherapy → surgery (Albain 1995 JCO) finding suggested that a pathologic complete response in 22% led to improved OS-3 at 27% in this group. Those patients who had pN0 disease after induction chemotherapy had MS of 30 months compared with those who had residual N2 disease. at 10 months.
Postoperative Radiation Therapy
Postoperative RT volumes in N2 disease include:
- bronchial stump
- ipsilateral hilum
- ipsilateral mediastinum.
- Total dose recommended is 50.4 Gy, 54-60 Gy for ECE or R1 resectionand 60 - 70 Gy for frank residual disease (R2).
Post operative radiation therapy (PORT) in patients with resectable NSCLC is the subject of debate. There is evidence that PORT does improve outcomes, in patients with N2 disease. There are ongoing Phase III prospective trials testing the role of PORT in pN2 patients.
LCSG 773 randomized controlled trial of PORT or observation (Weisenburger 1986, NEJM) This study randomized 210 patients to PORT or observation with Stage II-IIIA disease. Radiation therapy consisted of Co-60 or better RT to the mediastinum to 50 Gy on POD 28. Most of the disease in this study was squamous cell carcinoma. Overall local recurrence was better in the PORT arm at 3% compared with 41% in the observation arm. DFS was better in the PORT arm, but there was no difference in overall survival.
PORT Meta-analysis (Burdett, 2005, Lung Cancer) This is a controversial analysis. This study was a meta-analysis of 10 tirals of patients treated after 1965. This meta-analysis overall suggested that PORT was a detriment to OS. A subset analysis showed a detriment to overall survival in completely resected Stage I/II disease but no adverse effects in N2 disease. This study is highly problematic for a number of reasons.
PORT Meta-analysis Criticisms:
- 25% of patients were T1N0 (Stage IA)
- Staging techniques used in this study are no longer used
- Radiation therapy techniques are obsolete. Large fields, fraction sizes and high total doses, 60Co beams are no longer used.
- > 30% of the meta-analysis relied on a poorly done study using poor techniques and technology.(Dautzenberg 1999 Cancer) that showed PORT to be detrimental due to a high 5 year mortality from PORT at 31% compared to 8% mostly due to treatment related cardiac or respiratory deaths.
SEER analysis (Lally 2006 JCO) examined 7465 patients Stage II-III NSCLC treated between 1988 and 2002, with PORT or observation. With a median follow up of 3.5 years, overall PORT did not affect overall survival. However, for N2 disease PORT was associated with better OS (HR 0.85) but was detrimental for N0/N1 disese.
ANITA trial re-analysis (Douillard, 2008 IJROBP), a chemotherapy trial, but 232 patients received PORT. ANITA was a randomized controlled study of adjuvant CDDP/vinorelbine compared with observation for IB/IIIA disease after resection. Overall, as a group, PORT was detrimental to survival with a HR of 1.34. On subset analysis, based on pN stage:
- N0: PORT was detrimental.
- N1: PORT improved survival in observation arm but detrimental in the chemotherapy arm.
- N2: PORT improved survival in both chemotherapy and observation arms
INT-0115/RTOG 9105/ECOG (Keller 2000 NEJM) tested PORT compared with chemo-RT in resected Stage II or III NSCLC and found no difference in local control or overall survival at 3.2 years.
Postoperative Chemo-radiation Therapy
There were two sentinal trials that demonstrated the importance of adding chemotherapy to radiation in locally advanced Stage IIIA/B NSCLC. The CALGB 8433/Dillman Study and RTOG 8808/Sause Study. These two studies demonstrated significantly improved median survival, OS-2, and OS-5.
CALGB 8433 Dillman Regimen (Dillman 1990 NEJM) This study examined 155 patients with Stage IIIA (T3 or N2) lung cancer treated as follows:
- Radiation therapy alone to 60 Gy
- Sequential Chemotherapy (CDDP/vinblastine) → RT to 60 Gy
Sequential chemo-radiotherapy:
- improved median survival from 10 months to 14 months.
- improved OS-2 (2 year overall survival) from 13% to 26%
- improved OS-5 from 7% to 19%
RTOG 8808 (Sause 2000 Chest) examined 458 patients with unresectable NSCLC Stage II-IIIB in a 3 arm randomized trial:
- Radiation alone to 60 Gy @ 2 Gy/fraction
- Radiation alone to 69.6 Gy @ 1.2 Gy/BID
- Sequential chemotherapy (CDDP/vinblastine) → 60 Gy RT
The trial results were improved median survival in arm 3 with sequential chemotherapy. Median survival improved from 11.4 months (conventional fractionation) to 12.0 months (BID) to 13.2 months with sequential chemo-radiotherapy.
More recent studies following on Dillman and RTOG 8808 demonstrated the superiority of concurrent chemo-radiotherapy over consecutive treatment in inoperable Stage II-III NSCLC. The most important of these are the West Japan Lung Cancer Study Group and RTOG 9410 (Curran).
West Japan Lung Cancer Study Group (Furuse 1999 JCO) Concurrent compared with consecutive Chemo-radiation therapy.
West Japan Lung Cancer Study Group (Furuse 1999 JCO) Stage II/III NSCLC randomized to concurrent or sequential radiation therapy. This study and two arms: Concurrent and sequential and enrolled 320 patients. The arms of the Trial were:
- Concurrent: CDDP/vindesine/mitomycin C with split course RT 28 Gy per course x 2 courses
- Sequential Arm: CDDP/vindesine/MMC with 56 Gy RT no split .
OS and PFS were both better in patients with concurrent CRT. Median survival improved from 13.3 months in sequential to 16.5 months and OS-5 was 15.8% in the concurrent arm compared with 8.9% in the sequential arm.
RTOG 9410 (Curran 2003 ASCO) compared Dillman Regimen with concurrent CRT in a 3 arm trial. This study enrolled 610 patients and randomized them to 3 arms.
The three arms:
- Dillman Regimen: 63 Gy
- Concurrent CRT to 63 Gy
- Concurrent hyperfractionated CRT to 69.6 Gy @ 1.2 Gy BID.
Chemotherapy was CDDP/vinblastine in arms 1 and 2. Chemotherapy was CDDP/VP16 (EP) in arm 3.
Definitive concurrent chemo-radiation therapy (ARM 2) has a better median survival outcome. and a better OS-4.There was increased toxicity in the concurrent arm.
Results:
- Median survival: 17 months (Arm 2: CRT to 63 Gy/daily) 15.2 months (Arm 3: BID RT/Chemo) 14.6 months (Arm 1 RT alone)
- OS-4 21% in Arm 2 (concurrent chemo RT), 12% (in BID and RT alone) arms.
Concurrent chemotherapy with radiation adds toxicity to the treatment. CDDP/VP16 (EP - etoposide cisplatin) allows a full chemotherapy dose to be delivered with radiation. Carboplatin/taxol, gemcitabine, or vinorelbine require significant chemotherapy dose reductions during RT administration.
Induction chemotherapy as part of definitive chemotherapy has been examined by LAMP and CALGB and no benefit was found to neoadjuvant chemotherapy. Definitive chemo-radiation therapy (concurrently) remains the standard.
LAMP Phase II Neoadjuvant chemotherapy → ChemoRT Trial (Belani 2005 JCO)LAMP is a randomized Phase II trial with Stage IIIA/B NSCLC 3 arm trial of neoadjuvant chemotherapy followed by defintive chemo-RT. This Phase II trial randomized 276 patients into one of three arms:
- induction chemotherapy x 2 cycles → RT to 63 Gy (Dillman regimen)
- induction chemotherapy x 2 cycles → concurrent chemotherapy + RT to 63 Gy
- concurrent chemotherapy + RT → consolidation chemotherapy x 2 cycles.
- Chemotherapy in all arms was carboplatin/taxol.
Results demonstrated Arm 3, concurrent chemo-radiation followed by consolidation chemotherapy had a better outcome. Median survival was 16.3 months (arm 3) compared with 13 months (arm 1) or 12.7 months (arm 2).
CALGB 39801 Phase III Randomized trial of Induction Chemotherapy (Vokes, 2007 JCO). This phase III randomized 2 arm trial of induction chemotherapy enrolled 366 patients with unresectable Stage IIIA/B NSCLC randomized to:
- Concurrent chemo-radiotherapy
- Induction chemotherapy x 2 cycles → concurrent chemo-radiotherapy.
- Chemotherapy was carboplatin/taxol.
There was no difference in median survival or overall survival. Induction chemotherapy increased grade 3 - 4 hematologic toxicities.
Adjuvant/Ancillary Treatments
For patients experiencing a complete response to chemo-radiation therapy, an extremely controversial question arises. Should they undergo surgical resection after complete response?
The answer to this question is unknown, and there is no solid data to help make a decision. The best data to date comes from a subset of INT-0139 (Kathy Albain) patients who received chemo-radiation followed by a lobectomy. These patients did show a benefit, but does not answer the question whether adding surgery to chemo-radiotherapy is beneficial. The INT-0139/Albain study investigated adding surgical resection after neoadjuvant Chemo-radiotherapy and did show a benefit in local control, but without survival benefit.
INT-0139/Albain (Albain 2009 Lancet) Chemo-radiotherapy alone or CRT → Surgery This trial examined 396 technically resectable Stage IIIA patients randomized to induction chemo-radiation therapy followed by resection or definitive chemo-radiation therapy.
- 396 technically resectable Stage IIIA non-small cell lung cancer patients
- Randomized:
- Arm 1: induction chemo-radiation therapy (45 Gy (or 50.4 Gy with inhomogeneity correction) and CDDP/VP16 → surgery
- Arm 2: Definitive Chemo-RT alone
- Both arms were preceded with 2 cycles of CDDP/VP16 q28days
- Local control better in surgical arm (10% relapse compared with 22%
- No difference in distant mets
- No difference in overall survival.
A matched subset analysis examined patients treated with lobectomy and found and OS-5 benefit at 36% compared with 18% in the matched non-surgical arm. This advantage was not seen in those who had pneumonectomy. 26% of those undergoing pneumonectomy died, while only 1% died from lobectomy.
Is Pre-op chemotherapy alone adequate in Stage IIIA/B: Maybe.
Induction chemo-radiation therapy may not be absolutely necessary. Pre-operative chemotherapy alone may be adequate. There were two trials that attempted to examine this. A German trial that used a non-standard CRT regimen and a US trial that closed due to poor accrual. There is uncertainty that adding surgery to induction therapy is superior to definitive chemotherapy alone, and may come with associated toxicities. The two trials attempting to answer this condition are RTOG 0412/SWOG 0332 and German Lung Cancer Cooperative Group Trial.
RTOG 0412/SWOG 0332 Randomized Trial randomizing to induction chemotherapy ± Radiation therapy → surgery. This trial closed due to poor accrual.
German Lung Cancer Cooperative Group Trial (Thomas 2008 Lancet Oncol.) randomized 558 patients Stage IIIA/B to induction chemotherapy EP x 3 cycles → surgery → RT or Chemo-RT (BID RT with carboplatin/vindesine) → surgery. If positive margins or unresectable disease, the patient received more BID radiation. There was better pCR (60% compared with 20%) in the CRT group, but no difference in PFS or survival. If patients required a pneumonectomy post operative mortality in the CRT group was high.
- Randomized 558 patients with Stage IIIA/B NSCLC
- Randomization:
- Arm 1: EP x 3 cycles → surgery → RT
- Arm 2: chemo → CRT (BID RT with carboplatin/vindesine) → surgery
- Results: Greater pCR in CRT group at 60% compared with 20% in the induction chemo only group.
- No difference in PFS or survival
- If patients required pneumonectomy, mortality was higher in the CRT group.
Post Induction Surgery in IIIA Compared with Sequential RT after objective response: No Gain with surgery
If there is an objective response to induction chemotherapy in Stage IIIA disease, post induction surgery is not more beneficial than chemo-radiation therapy. This was studied by EORTC 08941 and reported in 2007.
EORT 08941 Trial of Stage IIIA disease treated with induction chemotherapy and randomized to radiation or surgery. (Van Meerbeeck 2007 JCO). This EORTC trial enrolled Stage IIIA patients.
- Stage IIIA patients enrolled
- All treated with induction chemotherapy with a response rate of 61%
- Randomized:
- RT to 60 Gy at 2 Gy/fx
- Surgery alone
- Only 50% had radical resection and only 5% had pCR, but 42% did have pathologic downstaging
- Operative mortality was 4% (at 30 days)
- There was only 55% compliance in the radiation arm.
- NO DIFFERENCE in OS, PFS.
The conclusion from EORTC 08941 is that resection is not more beneficial than radiation therapy after an objective response .
Surgical Resection in Stage IIIA/B lung cancers: Are outcomes better? Controversial.
In select patients with minimal non-bulky N2 disease eligible for lobectomy, a lobectomy may be beneficial after initial chemo-radiotherapy, based on the INT-0139 subgroup analysis. Local control rates for CRT are poor at about 50%, therefore surgery may, in these select cases be be useful.
Off protocol, consider induction chemotherapy for N2 disease or for those with poor performance status related to their disease. Preoperative chemo-radiation should also be considered for those with non-bluky but intermediate sized N2 nodes measuring 1.5 - 2 cm.
Superior Suclus Tumors
The general treatment paradigm for superior sulcus tumors (Resectable T3-T4 N0-1/ IIB-IIIA) per the SWOG 9417/INT-0160 is:
- Preoperative Chemo-RT → surgery → chemotherapy x 2 cycles (SWOG 9417) --OR--
- surgery → post-op RT to at least 55 Gy (Komaki 2000 IJROBP)
- If post-op and positive margins: postop ChemoRT should be hyperfractionated at 1.2 Gy BID to 60 Gy to avoid potential brachial plexus toxicity.
SWOG 9416/INT-0160 (Rusch 2007 JCO) Induction Chemo-radiotherapy + surgery for Superior Sulcus tumors. SWOG 9416 established the role of induction chemo-radiotherapy in superior sulcus tumors.
This trial was a Phase II trial which evaluated induction CRT → surgery for resectable T3/T4 N0-N1 Superior sulcus tumors.
SWOG 9416/INT-0160 Phase II Induction CRT → Surgery in SST
- Induction regimen was concurrent CDDP/VP16 + RT to 45 Gy → restage.
- If no progression: proceed to surgery → chemo x 2 cycles..
- Chemotherapy was cisplatin 50 mg/m2 days 1 and 8 and etoposide 50 mg/m2 d 1-5 repeated every 28 days for 4 cycles.
- 95% completed induction chemo-RT
- 80% had thoracotomy based on pre-operative judgement of resectability. 94% had complete resection.
- Findings: 56% pCR or near CR and OS-5 of 44% compared with 30% for historical controls.
- There was no difference between T3 and T4 tumors
Radiation Therapy in Superior Sulcus Tumors
Radiation therapy volumes are:
- GTV = PET + 2 cm margin and ipsilateral supraclavicular region.
- Technique is APPA
- Dose is 41.4 Gy then off cord to 45 Gy. Cord should not exceed 110% of prescribed dose.
Synchronous Disease
For patients with two synchronous nodules of identical histology in separate lobes, this should be considered and treated as M1 disease. If a different histology is found, the lesions may be considered synchronous Stage I NSCLC. Definitive surgery can be considered after full work up for metastatic disease.
Metastatic Disease: Brain Mets
Solitary brain lesions can be managed with surgical resection followed whole brain radiation therapy or with SRS and whole brain radiation therapy. Primary disease should be managed according to TNM staging (other than brain mets). Overall survival in those with solitary brain mets at diagnosis is still 20% - 40%.
Unlike small cell lung cancer, there is no clear role for prophylactic cranial radiation. Four randomized trials showed improvement in brain relapse rates to 19% from 9% but there was no survival benefit to adding prophylactic cranial irradiation. Cox, 1981 JAMA; Umsawasdi 1984, J.Neuroonc.; Miller 1998, Cancer Ther; Russell 1991 IJROBP. A meta-analysis in 2005 summarized these studies.
Dose Escalation
There is clear evidence that dose escalation improves local control and probably leads to better survival. Theses data begin with the following studies:
RTOG 73-01: Randomized Dose escalation study
- Randomized study of dose and timing:
- 40 Gy split course
- 40 Gy continuous course
- 50 Gy continuous course
- 60 Gy continuous course
- 60 Gy continuous course had the best survival and became standard.
- More recent studies have demonstrated the standard should be higher at 55 - 66 Gy
RTOG 9311 Dose escalation of RT alone 70.9 - 90.3 Gy
- Dose escalaton with radiation alone randomized to:
- 70.9 Gy
- 77.4 Gy
- 83.8 Gy
- 90.3 Gy
- 90.3 Gy dose found to be too toxic.
- 77.4 and 83.8 Gy found to be safe if V20 is 25-36% for 77.4 Gy and < 25% for 83.8 Gy.
- Local control was 50% to 78% with elective nodes failing less than 8%.
Michigan Dose Escalation (Spring Kong 2005 IJROBP)
- Dose escalation trial of 106 patients Stage I - III
- treated with 60 - 106 Gy at 2.1 Gy/fraction and 3D-CRT
- Treatment volume is primary tumor + involved LN + ≥ 1 cm margin
- No chemotherapy in 81%
- Median survival was 19 months.
- Multivariate analysis demonstrated RT dose was the only predictor of better survival.
RTOG 0117 and NCCTG 0028 Dose escalation + Chemotherapy and UNC Phase I/II trial of 60 Gy or 74 Gy have all demonstrated safety at 74 Gy.
CALGB 30609/RTOG 0617/NCCTG N0628/ECOG R0617 Intergroup Dose Escalation Trial
- Phase III randomized trial comparison of 60 Gy to 74 Gy with concurrent and consolidation carboplatin, taxol ± cetuximab in Stage IIIA/B NSCLC is accruing patients. No results are reported.
Endobronchial Brachytherapy
Various fraction schemes (15 Gy x 2, 8 Gy x 1, at 0.5 cm) have been used in previously irradiated patients with endobronchial disease causing symptoms. Complications can be significant including fatal hemoptysis in 5% - 10%, broncho-esophageal fistula in 2% and bronchial edema in 1%. Symptom relief is obtained in 80%.
MDACC (Delclos ME 1996 Radiology) published a series of 81 patients treated with endobronchial brachytherapy at 15 Gy x 2 at 6 mm over 2 weeks. Response rates were 84%. Patients with excellent response had better survival (MS 13.3 months) than those with poor response (MS 5.5 months). 2 fatal complications were reported due to fistula or tracheomalacia.
Palliation
Radiation is frequently used for palliation of symptoms in lung cancer. While there is no optimal dose/fractionation scheme known, it is likely that conventional fractionation is probably no better than hypofractionation. A Norwegian randomized trial examined 30 Gy at 3 Gy/fraction compared with 17 Gy in 2 fractions (8.5 Gy each) 1 week apart or 10 Gy in a single fraction. All achieved equivalent palliation. (Sundstrom, 2007 JCO)
Prognosis
The general survival outcomes for locally advanced non-small cell lung cancer (Stage IIIA disease) For patients with two (metachronous) primary lung cancers a few years after treatment of a first tumor, the OS-5 can be as high as 40%, depending on TN staging of the new lesion.
For IIIA T3N1 disease, overall survival at 5 years ranges from 20% - 25%. For those with N2 disease, the OS-5 drops dramatically to 5%. (Range 3% - 8%).
Toxicity
The rate of death from intercurrent disease following PORT in Non-small cell lung cancer with older techniques approached 20% - 30%. Death was mainly caused by cardiovascular or pulmonary damage from PORT. New data, respecting normal lung tissue tolerances suggest far lower toxicity and death from intercurrent disease rates between 2% adn 3%. There are two studies, one retrospective and another a reanalysis published recently. These data examined post operative cases and found the death from intercurrent disease rates much lower.
Machtay/U.Penn retrospective review (2001 JCO) examined 202 patients treated with surgery and PORT in a matched controls study. Machtay demonstrated the following:.
- Surgery + PORT DID: 13.4% Matched controls: 10%
- If RT dose < 54 Gy DID was 2%
- If RT dose ≥ 54 y, DID was 17%
ECOG 35990 reanalysis ( Wakelee 2005 Cancer): This reanalysis of 488 patients randomzed to PORT compared with PORT + chemotherapy with radiation doses to 50.4 Gy demonstrated DID in RT arm at 4 years of 12.9% compared with machted controls at 10.1%
Radiation pneumonitis occurs 3 - 6 months after radiation as a subacute reaction. Symptoms include
- chest pain
- shortness of breath
- fever
- hypoxia
Chest CT scan shows ground glass changes in lung parenchyma within the RT port. Verify good sP02 and supplement if needed. If symptomatic, treat with prednisone 1 mg/kg/day for 3 weeks followed by a slow taper. Use Bactrim for PCP prophylaxis.
Dose Constraints
V20 constraints are:
- NCCN: V20 < 37%
- MDACC: V20 < 40% (radiation alone); V20 < 35% (with CRT), based on Lee HK IJROBP 2003
Mean lung dose is < 15 Gy; max ≤ 20 Gy for definitive RT.
Brachial Plexus limit is 1 cc below 60 Gy with a maximum point dose < 66 Gy
Esophagus should have a mean dose < 34 Gy, with the esophagus contoured from the thoracic inlet to the GEJ. V60 < 33%, V50 < 50%, ≤ 45 Gy to the entire esophagus. The maximum point dose should be < 70 Gy.
Esophagitis Grade 3-4 occurs less frequently in sequential Chemo-RT at 4%. With concurrent Chemo/RT it rises to 22%.