Small Cell Lung Cancer

Background

Small cell cancers of the lung are part of a spectrum of cancers of neuroendocrine morphology. The spectrum ranges from low grade typical carcinoid to intermediate atypical carcinoids to high grade large cell neuroendorine and small cell lung cancers.

Small cell lung cancer accounts for about 15% of the newly diagnosed lung cancer cases or about 33,000 of the 220,000 lung cancer cases per year. SCLC accounts for 25% of of the 160,000 lung cancer deaths per year. The median age at diagnosis is 64 years with 25% over age 70. Tobacco is associated with 95% of the cases and incidence is expected to decline as the smoking population decreases. Cigarette use peaked in 1965 and has been steadily declining from 50% of the male population and 32% of the female population to 21% and 18% by 2005. SCLC rates peaked in 1984, and have been slowing declining since then.

SCLC is characterized by rapid growth and early metastases. Most patients present with symptoms due to the rapid early progression of disease. Presenting sysmptoms can be constitutional, Presenting symptoms commonly seen include:

1. fatigue with decreased physical activity
2. cough
3. dyspnea
4. diminished appetite
5. weight loss
6. pain
7. hemoptysis was seen in 14%

The disease is often a large central mass invading or compressing the mediastinum, with SVC obstruction present in 10%. SVC syndrome symptoms can be exacerbated by thrombosis in the SVC. Chest imaging shows hilar and mediastinal adenopathy. Peripheral lesions are uncommon.

Over 2/3 of SCLC patients present with metastases most commonly in the contralateral lung. They also present with bilateral malignant effusions, liver, renal, adrenal and bone marrow metastases. The brain is a common site of metastases at first diagnosis.

Neuro-endocrine abnormalities are also seen in paraneoplastic syndromes associated with SCLC. Eaton-Lambert Syndrome (pre-synapse acetylcholine gated calcium channels) causing motor weakness, encephalomyelitis, and sensory neuropathy (from anti-Hu antibody). Lambert-Eaton Syndrome is characterized b proximal motor weakness that improves with use, hyporeflexia and dysautonomia. EMG findings confirm the diagnosis.

Endocrine disorders associated with SCLC include Cushings Syndrome due to marked increase in exogenous ACTH, SIADH. SCLC accounts for about 75% of tumors associated with SIADH. Serum concentrations of ADH are elevated in the majority of SCLC patients, but SIADH is present in no more than 5%. Ectopic production of ANF contributes to disorders in sodium hemostasis. The primary treatment for hyponatremia is the treatment of the disease with chemotherapy.

Likewise, ACTH is elevated in 50% of those with SCLC, but Cushings Syndrome is only seen in about 5%. Hyponatremia and Cushings are adverse prognostic factors. These patients have very limited survival.

Paraneoplastic neurologic disorders seen in SCLC include sensory, sensorimotor, autoimmune neuropathies and encephalomyelitis. These syndromes are thought to be related to auto-immune mechanisms. Antinuclear antibodies that bind to SCLC and neuronal tissues have been identified. These symptoms may preceed diagnosis by months and may be an early clue to initial relapse. Small tumors can cause significant or profound neurologic syndromes and an aggressive search may be required to find them. Neuroendocrine effects are usually not related to tumor bulk, and does not improve with systemic chemotherapy.

Genetics

3p deletion occurs in 95% of the cases of SCLC. Important suppressor genes include FHIT and RASSF1A are inactivated by this deletion. bcl-2/C-myc amplification is also seen, but not considered an initiating events. Other abnormalities inlcude the loss of p16, loss of Rb and p53 mutations.

Workup and Staging

Staging

Staging determines prognosis and treatment. SCLC has an AJCC classification which is not used, in favor or modifications by the VA Lung Study Group staging of "limited" v. "extensive." VALSG defined "limited stage" as disease which can be contained within one radiation portal. Limited Stage is not without controversy. Plural effusions, supraclavicular adenopathy, or contralateral mediastinal adenopathy are debated.

Some studies have not found a difference between limited SCLC and limited SCLC with pleural effusions, provided: the effusion is a transudate, non-hemorrahgic and cytologically negative on repeat examinations. Malignant effusions are appropriately excluded as it is impractical to irradiate the entire hemi-thorax.

Workup

History and physical exam with emphasis on smoking history. If smoking history is present, then smoking cessation is essential to better outcomes. Discontinuation of smoking should be emphasized with full supportive resources. Lab studies and imagiing are part of the work up. MRI/Brain, CT/contrast of CAP, and PET/CT or bone scan are essential. If there is evidence of a pleural effusion, thoracentesis is necessary to determine the nature of the effusion which will restage from limited to extensive stage disease.

Treatment and Prognosis

For untreated disease, prognosis is grim and short. The VALSG found untreated extensive SCLC has a median survival of untreated extensive stage SCLC is 6 weeks. Median survival for untreated limited stage SCLC is 12 weeks.when comparing cyclophosphamide to placebo.

Treated, Median survival for limited stage disease improved to 19 - 23 months according to Turrisi. Slotman noted extensive stage improved to 5 - 7 months. About 1/3 of limited stage patients treated with combined modality therapy will survive 5 years.

Extensive Disease

Extensive stage disease is extremely chemotherapy sensitive. Various regimens have been used in the treatment of extensive SCLC with a median duration of response of 6 - 8 months. Primary chemotherapy regimens are EP (etoposide/cisplatin) or cytoxan/adriamycin/vincristine (CAV). If a complete response of distant disease is seen, then radiation to the chest may be considered.

Prophylactic brain irradiation has been shown to give survival benefit with at least a partial response to systemic chemotherapy in extensive disease.

Typical response rates to first line systemic treatment in extensive SCLC treated with first line therapy consisting of EP on 3 week cycles for six cycles. was 86%. Median survival improved to 14.7 months and toxicity was lower than CAV (cyclophosphamide/adriamycin/vincristine) previously used. As second line therapy EP response was 55%.

The median duration of response to first line therapy is about 6 - 8 months. Short interval recurrence is a poor prognostic harbinger. Second line chemotherapy salvage after recurrence yields around 4 - 5 months additional median survival..

Maintenance chemotherapy has been studied, but to date, only minor prolongation of response is noted, without improving survival and increasing toxicity. There is no significant benefit demonstrated to using maintenance chemotherapy and there is associated increased toxcity.

Limited Stage

Limited stage disease is defined by the IALCG as being confined to one hemithorax, without malignant pleural effusion, contralateral disease or metastases. Some studies have included ipsilateral and sometimes contralateral supraclavicular nodal metastases, in otherwise limited disease, but these otherwise limited disease patients carry a trend toward worse overall prognosis.

Combined modality therapy is used in SCLC which is quite demanding. Treatment of patients with KPS < 50 (ECOG > 3) requiring frequent medical care and age > 50 and a prior septic episode on chemotherapy increased the risk of death due to chemotherapy.

Combined modality therapy consists of EP + concurrent RT to 45 Gy @ 1.5 Gy BID (Turrisi,1998, NEJM) or 60 - 70 Gy @2 Gy/day (NCCN) or 61.2 Gy in 5 weeks at 1.8 Gy x 16 → BID @ 1.8 Gy BID for 9 days. (concomitant boost).

Turrisi clearly demonstrated in INT-0096 ((Turrisi 1998 NEJM) the superiority of altered fractionation with chemotherapy. He used EP x 4 cycles with concurrent RT at 1.5 Gy BID to 45 Gy over 3 weeks. All received PCI 20 25 Gy. OS-5 was better at 26% v. 16% (for once daily dosing at 1.8 to 45 Gy) and LC was better at 64% compared with 48%. There was increased grade 3 esophageal toxicity. Turrisi limited spinal cord dose in this fractionation scheme to 36 Gy. The NCCN recommends 41 Gy limits on BID or ≤ 50 Gy treatments in 3.2011.

Concurrent chemo/radiation is better than sequential chemotherapy/radiation therapy as has been shown by the JCOG 2002 study. The combined chemo-RT regimen improved median survival from 20 months to 27 months. OS-5 also improved from 20% to 30% a gain of 10%. NCIC Phase III data revealed early concurrent RT also was better than delayed RT. This data was followed by Jeremic in 1997 which showed early RT/Chemo better than delayed Chemo → Chemo/RT. Jeremic demonstrated both improved median survival at 34 months compared to 26 months in delayed RT/chemotherapy and better OS-5 at 30% over 15% which is double the delayed chemo/RT rate.

Meta-analysis of 7 Trials by Fried in 2004 (JCO)early RT < 9 weeks is better than late RT (> 9 weeks) after initiation of chemotherapy. There was 5.2% better OS-2 with early RT. DeRuysscher presented similar findings and Spiro affirmed with the caveat that delivery of concurrent chemotherapy should not be compromised. Overall, the results suggest that there is a moderate benefit for early Chemo/RT administered in cycles 1 - 3.

Dose Escalation

CALGB 8837 (Choi 1998 JCO) Phase I maximum tolerated dose study of 1.5 Gy BID to 45 Gy or 2 Gy qd to > 70 Gy. This study was updated and may show OS-6 better than BID at 36% compared with 20% in the BID regimen. CALGB 30610/RTOG 0538 comparing 45 Gy BID in 3 weeks per INT-0066 to 70 Gy at 2 Gy/day per CALGB regimen is ongoing. This is a 3 arm study in dose escalation. The arms are:

Jeremic (1999 JCO) examined consolidation chest RT after Complete Response to Chemotherapy in Extensive SCLC. In this trial, all patients recieved EP x 3 cycles. If a CR was seen at all distance sites, patients were randomized to accelerated hypofractionated RT to 54 Gy with concurrent carbo/etoposide or observation. Both arms received PCI and consolidation EP. Consolidation RT improved OS-5 to 9.1% from 3.7% and improved median survival 17 months compared with 11 months.There was a trend in favor of improved local control but no improvement in distant metastases free survival.

Treatment Fields and Recommended Doses

Classic Fields: GTV= gross disease + ipsilateral hilum, bilateral mediastinal lymph nodes from the thoracic inlet to 5 cm below the carina. CTV = GTV + 1.5 cm margin with 8 mm margin around elective hilum and mediastinal regions. PTV = CTV + 1 cm

CALGB 30610/RTOG 0538 3D-CRT/IMRT allowed. CTV includes GTV plus potential occult disease.

Thoracic radiation fields inlcude IMRT if V20 < 30% and FEV1 > 1 L. Otherwise, minimize the contra-lateral lung exposure with AP/PA fields to ≤ 15 Gy.

Prophylactic Cranial Irradiation

PCI is used with any response to chemotherapy in SCLC. This includes extensive stage disease treated solely with chemotherapy. EORTC 08993 (Slotman 2007 NEJM) examined 286 patients treated with extensive stage SCLC treated with chemotherapy, using symptomatic brain metastases as primary endpoin . Patients were randomized to ± PCI after any response to chemotherapy. Most PCI patients were given 20 Gy at 4 Gy/fraction. PCI lowered the risk of of symptomatic brain metastases and improved DFS and OS from 5.4 months to 6.7 months. OS-1 nearly doubled from 13% without PCI to 27% with PCI.

The EORTC 08993/Slotman study has been criticised for lack of pre-treatment MRI. The RT group was more likely to receive chemotherapy at the time of extra-cranial progression and 59% of the control group received WBRT for intracranial progression of disease.

PCI in limited stage SCLC (Auperin Meta-analysis NEJM 1999) compared ± PCI after CR following induction chemotherapy ± RT without evidence of brain metastases before randomization. He found a decreased 3 year incidence of brain metastases to 33% from 55% and improved DFS. There was a trend toward improved outcome with higher doses and with RT < 4 months from the start of chemotherapy.

PCI standard dose is defined by the RTOG 0212/Intergroup Trial (Lancet Oncol. 2009) at 25 Gy at 2.5 Gy/fraction.

RTOG 0212 compared doses in PCI. Standard doses are 25 Gy at 2.5 Gy/fraction in 10 fractions. RTOG 0212 compared 36 Gy at 2 Gy/fraction in 18 daily fractions or 24 BID 1.5 Gy fractions. There was no difference in brain metastases at 2 years, but there was an OS and chest relapse advantage in the standard (25 Gy) arm at 42% v. 37% p=0.05 due to greater cancer related mortality in high dose group.

Komaki (IJROBP 1995) and Arrigada (JNCI 1995) reported no difference ± PCI in randomized trials addressing neuropsychological changes. Most patients have abnormal neuropsychiatric testing after chemotherapy than with PCI.

The greatest 3 month Quality of Life assessment impact was alopecia and fatigue. Worsening emotional and cognitive function were also seen (Slotman 2009 JCO)

Presently, the treatment recommendation for PCI is limited or extensive stage, CR or PR after chemotherapy ± RT ± MRI brain. ECOG performance status of 0 - 2 (KPS ≤ 50 - 60, up and out of bed >1/2 time, minimal assistance). PCI should be administered within 3 - 6 weeks of the last cycle of chemotherapy.

Salvage

There is no clear role for definitive surgical resection in SCLC. Retrospective studies suggest T1-2 N0 disease may mayv reasonable outcomes with surgery and adjuvnet platinum based chemotherapy, but diseases diagnosed at this stage are extremely rare. 2/3 are metastatic at diagnosis, and limited stage disease accounts for most of the remainder. Less than 3% present with solitary nodules without mediastinal lymphadenopathy. Currently, JCOG has a Phase II trial which suggested surgical resection was possible for State I - IIIA disease → EP with OS-5 at 69%, 38% and 40% stage wise. There are ongoing randomzied trials in Europe and Japan.

If mediastinal nodes are identified after attempted surgical resection, surgery is followed by concurrent chemo/RT covering the mediastinal nodes. If nodes were negative then chemotherapy alone is recommended by the NCCN.

Topotecan has been demonstrated in randomized controlled trials at the time of recurrence for SCLC post-chemotherapy failure. Topotecan doubled survival time from 14 weeks to 26 weeks, compared with best supportive care. CAV (cyclophosphamide/adriamycin/vincristine) has been shown to be effective as second line therapy after EP recurrence/failure.

Doceltaxel, vinorelbine, gemcitabine are not effective against SCLC and have low activity. They are not used for these reasons.

Palliation -- Bleeding and SVC Obstruction

Palliative RT for SVC syndrome can be given in a few large fractions at 3 - 4 Gy/fraction followed by more conventional BID or daily fractionation schemes.

Hemoptysis, pain, cough and shortness of breath can be treated with 30 Gy in 10 fractions, 17 Gy in 2 fractions given a week apart, or 10 Gy in 1 fraction. Per a Norwegian Trial by Sundstrom (2007 JCO) all gave similar levels of palliation.

Toxicity

Follow up

SCLC follow up: HP, CT chest and labs at each visit q2-3 months for 1 year, then q3-4 months in years 2 -3 and then q 6m for years 4 -5, then annually thereafter. PET should be included whenever CT findings suggest recurrence or metastases.

Normal Tissue Dose Limits

Total Lung V20 with RT alone: < 40%; with chemotherapy < 35%.

Mean Lung Dose < 15 Gy ideally, but certainly < 20 Gy

Cord Dose Limits:Turrisi: 36 Gy. NCCN: ≤ 41 Gy (BID) and ≤ 50 Gy QD

Heart constraints: RT alone: V40 ≤ 50%; ChemoRT: V40 ≤ 40%

The main toxicity in the BID fractionation is acute Grade 3 esophagitis at 27% compared with 11% in daily treatments.

Esophageal Dose Constraints: RT alone: V60 < 50%; ChemoRT V55 < 50%, Ideally keep mean dose to < 34 Gy per RTOG 0538

Radiation Oncology Synopsis