Recent Advances in the Diagnosis and Treatment of Lung Cancer · RECENT ADVANCES IN THE DIAGNOSIS AND TREATMENT OF LUNG CANCER Non-smallcell lung cancer Non-smallcell lung cancer

Recent Advances in the Diagnosis andTreatment of Lung Cancer .

C K Ham, FRCP, K H Lim, MRCP, M M Wong, MRCP, Division of Respiratory Medicine,Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur

Epidemiology

Lung cancer, the most common cancer in theworld today is responsible for more cancer deathsthan any other solid tumours, World-wide, itaccounts for approximately 1 million deaths peryear, of which about 30% occur in developingcountries l

, Lung cancer is a rapidly growingproblem in many Asian countries2

, Smoking isresponsible for 78% to 87% of lung cancers3,4.

While there is a decline in smoking rates indeveloped countries" the continuously highsmoking rate in developing countries willcontribute to an increase in the incidence of lungcancer. In 1980, lung cancer accounted for 10 - 15%of all cancers in men in most Asian countries1

•

The incidence of lung cancer continues toincrease, especially in women. In many countries,including the United States, more women diefrom lung cancer than from breast cancer.

In the last two decades, there have been shifts inthe distribution of histological cell types thataccompanied changes in lung cancer incidence.In recent years, Kreyberg Type II lung cancers(adenocarcinoma, alveolar cell or undifferentiatedcarcinomas) and in particular adenocarcinotna ofthe lung are becoming more prevalent thanKreyberg Type I lung cancers (squamous cell,small cell or large cell carcinomas) in the West6

-10

.

Similar trends showing a relative increase ofadenocarcinoma compared to squatnous cellcarcinoma have also been noted in Asian

This article was accepted: 15 January 2001

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countriesll-14

• This change in the distribution oflung cancer histological cell types may be due tothe changing composition of the cigarette fromhigh to low tar and nicotine.

The most widely accepted lung tumourclassification schema is that of the World HealthOrganisation (WHO). The clasSification has beenperiodically updated. The most recent update waspublished in 1999" while the one prior to thatwas compiled in 1981". In the 1999 compilation,the broadest categories are .retained from theprevious schema. During the past decade, aconsiderable body of information onimmunohistochemical staining properties of lungcancer has been used to refine classicalmicroscopic classification. While in most cases,histological features alone are sufficient to guidetherapy, in a minority of cases tumours areinsufficiently differentiated or biopsies too smallto be classified by conventional histologicalmethods and immunohistochemical staining maypermit more accurate histological c1assification17

.

The great pessimism regarding the managementof patients with lung cancer has stemmed fromthe fact that there were few good options for theearly detection, prevention or treattnent of lungcancer in the past. In recent years, however, therehave been many advances in the early detection,staging and treatment of this disease that arebringing about a change in the nihilistic attitudeof doctors towards lung cancer patients.

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RECENT ADVANCES IN THE DIAGNOSIS AND TREATMENT OF LUNG CANCER

Non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for80 to 85% of all lung cancer cases. The mostcommon cell types are adenocarcinoma,squamous cell carcinoma and large cellcarcinoma. Surgical resection is the best chancefor cure in patients with localised NSCLC, i.e.,clinical stage 1 and II disease. Unfortunately, 70%or more of all NSCLC patients present with locallyadvanced (stage III) or disseminated (stage IV)disease18

• Some may have co-existing medicalconditions that lnake them unsuitable candidatesfor surgery.

Revision in the International System forstaging non-small cell lung cancer

Based on the analysis of a collected database of5,319 patients treated for primary lung cancer, theUnion Internationale Contre Ie Cancer andAmerican Joint Committee on Cancer haverevised the TNM staging of lung cancer to moreaccurately reflect the appropriate treatmentoptions and prognosis of the various subsets(Figure 1 and Table I)". Changes from theprevious system include the division of stage Iinto two categories CIA and IB) based on tumoursize, and the division of stage II into two

Table ICumulative Survival of Non-small Cell Lung Cancer Patients According to Stage of Disease"

Months after Treatment (Cumulative %surviving)

Stage TNM subset 12 (%j 24 (%j 36 (%j 48 (%) 60 (%jClinical stage'IA T1 NO MO 91 79 71 67 61IB T2 NO MO 72 54 46 41 38IIA T1 N1 MO 79 49 38 34 34liB T2 N1 MO 61 42 34 26 24

T3 NO MO 55 37 31 27 22iliA T3 N1 MO 56 17 12 9 9

Tl-3 N2 MO 50 26 19 15 13IIiB T4 NO-2 M1 37 15 10 8 7

Tl-4 N3 MO 32 11 6 4 3IV Any Tany N M1 20 5 2 2 1

Surgical-pathological stage"IA T1 NOMO 94 86 80 73 67IB T2 NO MO 87 76 67 62 57IIA T1 N1 MO 89 70 64 61 55liB T2 N1 MO 78 56 47 42 39

T3 NO MO 76 55 47 40 38iliA T3 N1 MO 65 38 30 30 25

Tl-3 N2 MO 64 40 32 26 23, Clinical stage as determined by pre-treatment clinical and imaging evaluation (based on data of 5,230 patients)" Surgical-pathological stage which depends on intra-operative assessment by the surgeon and post-operative

assessment by the pathologist (based on data of 1,910 patients)

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CONTINUING MEDICAL EDUCATION

Primary tumour(T) Regional lymph nodes(N)

TX Primary tumour cannot be assessed, or tumour proven by the NX Regional LNs cannot be assessedpresence of malignant cells in sputum or bronchial washings but nolvisualised by imaging or bronchoscopy NO No regional LN metastasis

TO No evidence of primary tumour N1 Ipsilateral peribronchial LNsipsilateral hilar LNs

Tis Carcinoma In situ intrapulmonary LNs by direct extension of primary tumour

T1 Tumour::::3 em in greatest dimensions, surrounded by lungar visceral N2 Ipsilateral mediastinal LNspleura, without bronchoscopic evidence of invasion more proximal slIbcarinal LNsthan the lobar bronchus (Le. not in the main bronchus)

N3 Contrala/eral hiler LNsT2 Tumour >3 em in greatest dimension contralateral mediastinal LNs

or involves main bronchus but.:::.2 cm distal to canna ipsilateral or contralateral scalene or supraclavicular LNsor invades the visceral pleuraor associated with atelectasis or obstructive pneumonitis that extentsto the hilar region but does not involve the entire lung

Distant metastasis (M)T3 Tumour of any size lhat directly invades lhe chest wall (incl. superior

sulcus tumours), or diaphragm, or mediastinal pleura, or parietal MX Presence of distant metastasis cannot bepericardium, or phrenic nerve; assessedor in the main bronchus within 2 em of carina without involving the MO No distant metastasiscarina M1 Distant metastasis presentor associated with atelectasis or obstructive pneumonitis of the enUre Separate metastatic tumour nodule(s) in ipsilaterallung non-primary tumour lobe(s) oflhe lung also classified as M1

T4 Tumour of any size that invades the mediastinum, heart, great vessel,recurrent laryngeal n., trachea, oesophagus, vertebral body, or carina; TNM subsetsor the presence of a malignant pleural or pericardial effusion

Stage TNM subsetor the presence of satellite tumour nodule(s) within the primary tumourlobe of the lung 0 TIs NO MO IliA T3 N1 MO

IA T1 NO MO T1-3 N2 MO

IB T2 NO MO IlIB T4 NO MO

IIA T1 N1 MO T4 N1-2 MO

liB T2 N1 MO T1-4 N3 MO

T3 NO MO IV AnyT Any N M1

Fig.l: International Staging System for Lung Cancer".

categories (IIA and lIB) based on tumour size andnodal status. The category T3NO has been movedfrom stage IlIA to lIB. Tumours classified as T3are neoplasllls that have grown beyond the lungparenchyma to involve structures still amenableto resection, while T4 defines those tumours withextensive extrapulmonary extension, usuallyprecluding curative or complete resection.Satellite tumour nodules in the same lobe as theprimaly tumour are now also classified as T4while separate metastatic tumour nodules in theipsilateral, non-primary tumour lobe are nowclassified as Ml.

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The importance of accurate lung cancerstagingOnce lung cancer is diagnosed~ accurate staging isessential for therapeutic decision lllaking andestimation of prognosis. It is important toaccurately differentiate stage I to IlIA (potentiallyresectable) hom stage IIIB to IV (non-resectable)cancer. Following surgical resection, both localand distant relapse rates increase with increasingT and N stages and distant failure is more commonthan local failure. Adenocarcin01llas and large cellundifferentiated carcinomas are more likely tospread distantly than squamous cell carcinomas.


RECENT ADVANCES IN THE DIAGNOSIS AND TREATMENT OF lUNG CANCER

The accurate evaluation of nodal status requiresinvasive staging with mediastinoscopy or a variantof this procedure. The disappointing false-positiveand false-negative rates associated with computedtomography (CT); about 50% and 20%,respectively20 have resulted in the search for a moreaccurate non-invasive procedure. Nodal stagingstudies using positron emission tomographic (PEl)scanning with 2-fluoro-2-deoxy-D-glucose (FDG)have shown correct diagnosis and staging in 94%and 96% of cases, respectively, compared to 61%and 79% of cases evaluated by CT. A negativemediastinum on PET FDG scan reduces the needfor mediastinoscopy21.23, However, PET scanningfacility is not widely available.

After stage, the next important prognostic featuresare performance status, weight loss, and gender(female patients fare better than male), in thatorder2<1, Age does not appear to be a majorindependent risk factor.

The role of chemotherapy in the treatment ofnon-small cell lung cancer

The general pessimism regarding lung cancerchemotherapy and prognosis is probably relatedto results of studies in the early 1980s thatalkylating agents in lung cancer chemotherapyactually reduced survivap5,26, However, clinicaltrials investigating the treatment of non-small celllung cancer (NSCLC) have shown significantimprovement in survival with the use of newchemotherapeutic agents and multi-modalitytreatmenF6

, A survey of British physiciansidentified that physician beliefs did not resonatewith current medical knowledge and portrayed anegative impression of NSCLC prognosis27, Anihilistic attitude toward the prognosis of patientswith NSCLC may result in both the underuse ofpotentially beneficial therapies and delay in thewidespread adoption of newer therapies. A 1998article appealed to the medical community tochange its nihilistic attitude toward the prognosisof patients with NSCLC in light of the findings ofnew chemotherapeutic studies26,

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The role of chemotherapy in the management ofNSCLC is well-established'"'''. A meta-analysisrevealed that cispIatin-based chemotherapyprovided a modest survival benefit in virtually allstages of NSCLC, including stage IV disease".Compared to the best supportive care alone,cisplatin-containing chemotherapeutic regilnensextend the median survival time by 2 to 4 monthsand increase the I-year survival rate by 10 to15%, With modern chemotherapy, mediansurvival averages 9 to 10 months in advancedNSCLC", a figure comparable to that achievedwith treatment of extensive-stage small-cell lungcancer, a malignancy which is viewed aschemotherapy-sensitive. Despite widespreadperceptions to the contrary, combinationchemotherapy improves the quality of life inpatients with NSCLC Even when there is no overttumour regression, tumour-related symptomssuch as cough, dyspnoea, chest pain andhaemoptysis . frequently improve followingcombination chemotherapy". In stage IV NSCLC,chemotherapy prolongs survival and providesrelief of symptoms in a significant percentage ofpatients30

, The American Society of ClinicalOncology recommends chemotherapy for NSCLCpatients with stage III and IV disease who havegood performance status18

,

Patients with poorer performance status havehigher risk of developing life-threatening toxicitywith chemotherapy. Survival is also directlycorrelated with performance status. While patientswith an Eastern Cooperative Oncology Group(ECOG) performance status of 0 survive an averageof approximately 9 month following cisplatinbased chemotherapy; those with an ECOGperformance status of 1 have a lnedian survival ofabout 6 months; and those with a performancestatus of 2 have a much shorter median survivalaveraging about 3 months31 , In view of these data,chemotherapy in advanced stage NSCLC, shouldbe resetved for patients with good performancestatus and rarely for patients with performancestatus 3 or 429,32, The optimal number ofchelnotherapy courses is controversial butextrapolating from small cell lung c;ancer, it seems

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reasonable to discontinue chemotherapy after foul'to eight cycles of treatment unless there is evidenceof continued tumour shrinkage and the patient istolerating chemotherapy without major adverseeffectsHl

•29

• The American Society of ClinicalOncology guidelines state that platioum-basedchemotherapy prolongs survival in patients withgood performance status and should be startedearly while the patient still has a good performancestatus and the duration of chemotherapy shouldnot exceed eight treatment cycleslB

,

Compared to thoracic radiotherapy alone theaddition of chemotherapy to thoracic radiationsequentially or concurrently in unresectable stageIII NSCLC clearly improves the long-term survivalratc, especially in patients with good performancestatus and less than 5% weight 108533,34. Recentstudies indicate that chemotherapy followed bythoracic radiotherapy improves 5-year sU1vival bythree to fourfold. The American Society of ClinicalOncology guidelines also recommends combinedchemotherapy plus thoracic radiotherapy inpatients with unresectable stage I1INIIIB NSCLCrather than thoracic radiotherapy alone lll

,

Increased local tUlnour control by radiotherapycombined with decreased distant metastasis bysystemic chemotherapy is the paradigm. Theeffectiveness of cytotoxic chemotherapy andradiation therapy is inversely related to tumourburden; for any given level of treatment intensity,small amounts of tumour are more likely to beeradicated than larger ones,

The role of neoadjuvant and adjuvantchemotherapy in non-small cell lung cancer

The 5-year survival rate in stage IIIA-N2 disease isapproximately 5% - 10% for patients treated withsurgery plus radiotherapy. Induction orneoadjuvant therapy can be defined ascytoreductive therapy administered beforedefinitive locoregional therapy. Cytoreductivetherapy consists of either chemotherapy orradiotherapy or combined chemoradiotherapy.The aim of cytoreductive therapy is to downstageprimary tumours and hence, increase the

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resectability rate. Neoadjuvant (pre-operative)chemotherapy may eradicate micr01netastases,rendering subsequent surgical resection possibleand improve long-term survival. Although the roleof neoadjuvant or induction chelnotherapy needsto be better defined by large studies, threerandomised control studies with a maximum of 30NSCLC patients per treatment arm havedemonstrated improved survival followingneoadjuvant chemotherapy3S-37, Rossell et aI 35 ,3B ina study involving 60 patients with stage IIIAshowed that preresectional chemotherapy with 3courses of cisplatin, ifosfamide and mitomycinoffers a significant long-term survival benefitcompared to surgery without prior inductionchemotherapy, Patients treated with neoadjuvantchemotherapy plus surgery had a median overallsurvival time of 26 months and a 3-year survivalrate of 25% in comparison to 8 months and 3%,respectively, for patients treated with surgeryalone (p < 0.001 for median survival time)35,38,Roth et al 36 compared surgery alone with perioperative chemotherapy consisting of threepreoperative courses of cisplatin and etoposide,followed by surgery, and then an additional threecourses of chemotherapy, The 3-year sUlvival ratewas 56% for patients treated with peri-operativechemotherapy and 150/0 for patients treated withsurgery alone. For induction therapy, the currentreference standard is platinuln-basedchemotherapy and thoracic radiotherapy".

The role of adjuvant (post-operative)chemotherapy following resection of NSCLCremains controversial and is not routinelyrecomlnended in patients with completelyresected stage I and II NSCLC10 because nosurvival benefit is observed followingpostoperative adjuvant radiotherapy,chemotherapy or chemoradiation in a recentreview of adjuvant and neoadjuvant trials byEinhorn"l, As the new chemotherapy drugs suchas paclitaxel, docetaxel, vinorelbine andgemcitabine improve survival in advancedNSCLC26

, compared to older agents, results ofadjuvant and neoadjuvant trials withchemotherapeutic regimens using these neweragents may be better and are eagerly awaited.

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Ongoing studies are evaluating the optimal typeand timing of chemotherapy and the role ofradiation therapy both before and after surgicalresection of stage lIlA N2 disease.

The role of radiation therapy in non-smallcell lung cancer

Radiotherapy is effective for the control of localdisease and is valuable for palliation ofsymptoms such as haemoptysis, cough, shortnessof breath and pain. There is a linear correlationbetween radiotherapy dose and local control ofNSCLC42 • Based on studies conducted more than20 years ago, radiotherapy alone affordsintrathoracic control in up to 50% of NSCLCpatients with locally advanced disease, provideda total dose of at least 60 Gy is employed".Several phase III trials and a meta-analysisdemonstrated the superiority of combinedmodality treatment with chemotherapy andradiotherapy of locally advanced, unresectablestage III NSCLC over radiotherapy alone44-46. Inthe meta-analysis which included data from 2,589patients with locally advanced, unresectableNSCLC, the addition of chemotherapy toradiotherapy sequentially or concurrentlyespecially in patients with good performancestatus extended median sUlvival from 10.3 to 12.0months and a fourfold increase in 2-year survivalrates3Q,42,4G, This is because many patients withlocally advanced (stage Ill) NSCLC developrecurrent disease outside the chest when they aretreated with thoracic radiotherapy alone.However, combined modality treatment withchemotherapy and radiotherapy is accolnpaniedby increased host toxicity such as oesophagitisand pulmonalY toxicity, and the optimal methodand sequence of radiotherapy administrationwith other treatment lllodalities have not beendetermined. In a study which comparedsequential with concomitant chemoradiotherapy,Takada et at showed superior results with theconcomitant regilnen over the sequential regimenin terms of response (84% versus 66%), mediansurvival (16.5 months versus 13.3 months) and


three-year survival rate (27% versus 12.5%)47,Similarly, the Radiation Therapy Oncology Groupin a three arm 600 patient trial cOlnparinginduction chemotherapy with cisplatin/vinblastine followed by standard radiationtherapy (60 Gy at 2.0 Gy per fraction) with twoconcurrent regimens, one based on the samechemotherapy and another using cisplatin/oraletoposide with hyperfractionated irradiationusing 1.2 Gy twice daily to a total close of 69.6 Gyin 6 weeks, showed a statistically significantimprovement in survival with concurrentchemotherapy compared to sequentialchemotherapy and irradiation"8.

Preoperative radiotherapy with doses more than45 Gy increases the operative morbidity andmortality and should not be used alone or withchemotherapy49, However, preoperativeradiotherapy may be beneficial to patients withPancoast tumour.

Although postoperative adjuvant thoracicradiation therapy after complete resection doesnot confer survival benefit, it reduces localregional recurrences50 , Therefore, it may beadvisable to irradiate these patients postoperatively in order to maintain their quality oflife for the longest possible time. However, somemay prefer careful observation and periodicchest radiographs, with radiotherapy reservedfor patients with regional failure because arecent meta-analysis of nine randomisedcontrolled studies including 2,128 patientsshowed a worse survival in patients with stage Iand II completely resected NSCLC receivingpostoperative radiotherapy51,

New radiotherapy strategies

New strategies designed to enhance local tumourcontrol including the use of radiation-sensitisingdrugs (such as cisplatin, paclitaxel, gelncitabineand topoisomerase-inhibiting agents), threedimensional radiotherapy planning techniques, oraltered radiation fractionation schedules lnayfurther improve survival outcome. With three-

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dilnensional treatment planning, total radiationdoses can be escalated to as high as 85 to 90 Gywithout causing major damage to normaltissUCS52.53. Another ll1Cthod of increasingradiotherapy dose while minimising normal tissuetoxicity is the use of multiple daily fractions51

. TheBritish CHART (continuous hyperfractionatedaccelerated radiotherapy) trial showed thathyperfractionated radiation therapy yields betterresults than conventional radiation therapy inpatients with unresectable NSCLC in tenus ofimproved local tumour control, reduced distantmetastasis and better median and long-termsurviva155 , In that study, CHART which consistedof thrice daily 1.5 Gy fractions of irradiation givenfor 12 consecutive days (36 fractions) to a totaldose of 54 Gy was compared with standard dailyradiotherapy (total dose, 60 Gy in 30 fractions).Combining chemotherapy with newer techniquesof thoracic radiotherapy may provide additionalsurvival benefit56•

New cytotoxic agents for non-small cell lungcancer

Newer cisplatin-based regimens containing thetwo taxanes paclitaxel and docetaxel; vinorelbine,a semisynthetic vinca alkaloid mitotic spindleinhibitor; the nucleoside analogue anti-metabolitegemcitabine or the camptothecin derivativetopois01nerase-l-inhibitors topotecan andirinotecan (Table II) are more effective and lesstoxic than older cisplatin-based combinationregimens with etoposide or vindesine and havebeen shown to yield responses in 40 to 50% ofpatients26 and improved survivaI57

-59 . None of thenew cisplatin-based two-drug combinations(doublets) is clearly superior, with respect toefficacy or toxicity, over the other. The SouthwestOncology Group and the ECOG are conducting adirect comparison of five of the newcombinations to determine the most effective andleast toxic combination32

• Meanwhile, thepreliminmy results of a study employing a tripletregimen containing cisplatin, gemcitabine andvinorelbine CPGV) have shown it to be superior tothe doublet regimen containing cisplatin and

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vinorelbine CPV) in terms of a significantimprovement in survival; median survival timewas increased by more than 3 months with thetriplet regimedJil

• The response rate to the PGVregimen was 57%. The median survival time forpatients treated with PGV was 51 weekscompared to 35 weeks for patients receiving PVand the 1-year probability of survival was 45%and 34%, respectively; while haematological andnon-haematological toxicities were not worsewith the triplet regimen60•

Although carboplatin, a less toxic analogue ofcisplatin, has never been compared head-to-headwith cisplatin, one can appropriately substitutecisplatin with carboplatin (with dosing accordingto renal function)61 in the treatment of NSCLCpatients29. Randomi'ied controlled trials involvingpatients with metastatic NSCLC showedcarboplatin given in combination with otheractive drugs yielded equivalent or superiorsurvival rates compared with an identical regimencontaining cisplatin62,63. In circumstances such asrenal dysfunction, pre-existing neuropathy or preexicting heart disease which make it impossible toadminister cisplatin because of its requirement forintravenous hydration, carboplatin is analternative to cisplatin.

As regards non-platinum-based doublet regimensusing the new agents, the combination ofvinorelbine and gemcitabine has been the mostextensively studied in Phase III trials. Responserates have ranged from 22% to '72% in patientswith stage lIIB and N NSCLC. The mediansurvival has ranged from 8 to 12 months and theregimen was well tolerated by the patientsM ,65. Forpatients with poor performance status andespecially for elderly patients, these newcytotoxic agents with hlgh single agent activity(Table II) and favourable toxicity may offerattractive chemotherapeutic options for palliationin advanced NSCLC, both in combination and assingle agent therapy. Despite the largelyundefined role of second-line chemotherapy forgood performance status patient who relapseafter initial treatment with a platinum-basedregimen, several trials have shown some of these

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Table IIPhase II Trial with New Cytotoxic Agents for NSCLC"

Drug No. of Patients Response Rate ("!o) Median Survival (week) I-year Survival ("!o)Paclitaxel (Taxol') 26DocetaxeIITaxotere') 26Vinorelbine 621 20 33 24Vinorelbine/cisplatin 328 41 38 35" 40Gemcitabine 572 21 41 39Gemcitabine/cisplatin 245 47 57 61Topotecan 13Irinotecan 138 27 35 Not reportedIrinotecan/cisplatin 185 44 34 Not reported

new drugs such as docetaxel and gemcitabinealso have considerable activity when used forsecond-line therapy".

Small cell lung cancer

Small cell lung cancer (SCLC) is rapidly fatal if leftuntreated, with most patients surviving less than 6months. SCLC differs from other types of lungcancers in its biological characteristic of a moreaggressive clinical behaviour and a rapid tumourdoubling time. Tumour doubling times as low as 23days have been reported for SCLC"·"'. In contrast,tumour doubling times of 88 days for squamous cellcarcinoma and 161 days for adenocarcinoma havebeen reported"'''. Unlike NSCLC, SCLC is usuallydisseminated at the time of diagnosis and istherefore not amenable to cure with surgery orthoracic radiotherapy alone. The vast majority ofpatients have stage IlIA, I1IB or IV disease atdiagnosis. In rare circumstances, surgical resectionmay playa potentially curative role in the occasionalpatient who presents with a solitary pulmonarynodule7D-n. As such patients still have a chance ofdeveloping systemic disease after surgical resection,it is currently recommended that they receivechemotherapy". In a Canadian study, the 5-yearsurvival after surgical resection was 51% for patientswith stage I disease, 28% for those with stage II, and19% for patients with stage III disease73

•

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As proposed by the Veteran's AdministrationLung Cancer Study Group, a two-stageclassification is used to stage patients as eitherhaving limited or extensive disease74

. Limitedstage disease is confined to one hemithorax withor without ipsilateral supraclavicular lymph nodemetastases and encompassed in one radiationport, while extensive-stage disease compriseslesions at sites beyond the definition of limiteddisease. Sixty to 80% of patients with SCLC haveextensive disease at presentation. The MayoClinic and North Central Cancer Treatment Groupdatabase, which includes 1,617 patients in clinicaltrials, documented a median survival of 15.1months for limited disease and 9.3 months forextensive disease with treatlnenCs. The overallsurvival for limited disease and extensive diseaseis 29% and 8% at 2 years, 12% and 2% at 5 years,and 4% and 1% at 10 years, respectively7s.

Chemotherapy in small cell lung cancer

Combination chemotherapy is the lnainstay ofSCLC management. Although multiple regimenssuch as cyclophosphamide/doxorubicin/vincristine (CAV), cisplatin/etoposide (PE) andCAV alternating with PE yield approximatelyequivalent survival results, FE appears to havethe best therapeutic index with fewer episodesof life-threatening toxicities2s,7o,76. PE, therefore

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has become the standard treatment for SCLCpatients, regardless of the stage at presentation70

,

Also, PE is more easily adnlinistered withconcurrent radiotherapy than othercombinations. In situations where pre-existingrenal dysfunction or neuropathy exists oraggressive hydration is a problclll, carboplatinmay be substituted for cisplatin without apparentloss of therapeutic efficacy77.7H. The combinationof carboplatin and etoposide is now oftenemployed to treat SCLC patients79

,

Despite high initial response rates of 65 to 95%depending on the stage of disease, relapse andprogression occur in the majority of SCLCpatients. Patients with extensive disease respondto combination cytotoxic chemotherapy lesswell than those with limited disease25 . Patientswith limited-stage disease receivingchemotherapy sometimes are cured, but in themajority of patients the median survival islimited to 15 to 20 months and the two yearsurvival rate is 40%". The probability of longterm (read as 5-year) survival usually does notexceed 5% in the overall SCLC population. Theoptimal duration of chemotherapy in SCLCremains controversial but the available dataindicate that four to six cycles of chemotherapyis sufficient to achieve, optimal outcome,regardless of response category or initialstageZS,70. Although SOlne reports indicate animprovement in disease-free survival withmaintenance chcmotherapy~O, overall survival isnot improved with treatment beyond four to sixcourses of chelnotherapy. Furthermore, qualityof life is diminished with continued treatment81

•

Recently, ECOG investigators reported excellent5-year survival results in limited stage SCLCusing just four cycles of PEl!2. Ten to 30% ofpatients with progressive disease may respondto salvage chemotherapy regimens but theremissions are usually short-lived. A favourableresponse to salvage chemotherapy is most likelyin patients experiencing at least a 3-monthinterval after cessation of inductionchemotherapy and development of recurrentdiseaseR3 • In CAY failures, PE generally effects

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response rates between 40 to 50%. Conversely,CAY generally is ineffective in PE failures,inducing relnissions in less than 15% ofpatients83

•

In chemotherapy naIve SCLC patients withpoor performance status, single-agentetoposide given either as a protracted lowdose or 5-day oral or intravenous regimen hasbeen found to be equally effective as multiagent intravenous chemotherapy for thepalliation of symptoms but inferior to the latterin terms of survivalR1

•R5

•

Preliminary studies on the use of high-dosechemotherapy and peripheral stem cell supportin SCLC show that this relatively new approachproduces better results in terms of response andsurvival when compared to conventionalchemotherapy86. In this treatment method, oneto three cycles of high-dose inductionchemotherapy is followed by granulocytecolony stimulating factor given at a dose of 300pg per day for 5 to 6 days to mobilise peripheralblood stem cells.

Radiotherapy in small cell lung cancer

A meta-analysis has shown that thoracicradiotherapy is of benefit in patients with limlteddisease SCLCR7. Therefore, thoracic radiotherapy isan essential component of optimal managementin limited-stage disease SCLC". With the additionof chest radiotherapy to combinationchemotherapy, the survival of patients withlimited-stage disease is further prolonged to 12 to20 months". Radiotherapy when administeredconcurrently with PE may provide a survivaladvantage but not when administeredconcurrently with cyclophosphamide-basedchemotherapy7o. 'Takada et al 88 reported animpressive survival advantage for concomitantradiotherapy compared with radiotherapydelivered sequentially following completion ofthe same combination chemotherapy withcisplatin and etoposide.



Fat<ll tumour burden

10"'1 cenjL-----'---c.--------"Onset of Diagnosistumour & therapy

~Y..~~ L Mo.l.o---J

Visible on X-ray (1 em' volume)

Progression of lung cancer".

<;;

8~ 10"11 9

~ .~

~ g 10'/1 mg

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Fig.2:

It is well known that the following factorsconnote a higher risk for the development oflung cancer: smoking~ chronic obstructivepulmonary disease, exposure to occupationalcarcinogens such as asbestos, previous tobaccorelated cancer, family history ancl femalegender91

.95 . One may argue that recommendinglung cancer screening would undermine theimpact of smoking cessation efforts. However,lung cancers occur also in individuals who havequitted smoking. In fact~ the risk of lung cancerremains elevated two-fold 15 years after smokingcessation96 . Even if all cigarette smokers were toquit smoking today~ it would take 20 years beforethe resulting decrease in mortality from lungcancer become fully evidenFs.

intuitive appeal, screening for lung cancer has notbeen demonstrated to decrease overall mortalityfrom the disease. A successful lung cancerscreening strategy needs to detect the disease in apreclinical stage when it is alllenable to curativetreatment, in contrast to its poor overallresponsiveness to treatment after it becomesclinically detectable (Table I), The best evidencefor the success of a screening strategy is areduction in mortality.

Screening and early detection of lung cancer

There is no question that the earlier lung canceris diagnosed and treated~ the better are thepatient's chances of survival (Table 0 19,9

1,9

2, There

is sufficient evidence of a prolonged pre-clinicalphase in lung cancer. Clones of endobronchialcell populations accumulate genetic mutationsleading to a progressively more malignant andultimately invasive malignant state. With ourcurrent diagnostic technology~ by the time lungcancer reaches a point at which it is clinicallydetectahle, the disease is already in the late stagesof its natural course and is only a couple ofdoublings away from reaching a lethal tumourburden. At the time of diagnosis~ lung cancertU1llour burden typically exceeds 109 cells (a l-cm3

volume) (Figure 11)93, An important goal for lungcancer managelllent, therefore, is to improve ourdiagnostic techniques to identify the premetastatic phases of lung cancer when the diseasecan be more successfully treated. Despite its

In a meta-analysis based on data on 987 patientswith SCLC from seven trials comparingprophylactic cranial irradiation (PCI) in dosesranging from 24 - 40 Gy given in 8 - 20 fractionswith no PCl in patients in complete remissionafter induction chemotherapYl PCI resulted in atTIoclest but significant 5.4% increase in the overallsUlvival rate at 3 years 05.3% in the control groupVS. 20.7% in the treatment group)S9. PCI alsosignificantly increased the rate of disease-freesurvival and decreased the cumulative incidenceof brain metastases by about 50%89, Larger dosesof radiation was found to have led to greaterdecreases in the risk of brain metastases, whilethe effect on survival did not differ significantlyaccording to the different radiation doses. On thebasis of these data, it is now reasonable to includePCI as part of the standard treatment of patientswith limited disease, SCLC who are in completeremission after chemotherapy. However, there islittle evidence that it provides any benefit inpatients with limited disease who fail to respondcompletely to systemic chemotherapy'",

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Screening with chest radiograph and sputumcytology

The role of screening with plain chest radiographs(CXR) remains controversial. In a review byStrauss et a1 97 , the fOUf trials (three NationalCancer Institute [NeI] trials98 and one fromCzechoslovakia"') published to date examined theaddition of sputum cytology testing to CXR or lessversus more frequent screening with SPUtU1ll

cytology testing and a CXR. All four studiesincluded men older than 40 years and all repoltedno benefit in survivaL Although screening withCXRs did detect more stage I lung cancers, theoverall lung cancer mortality rate was notchanged. In the NCI trials in the 1970s and1980s"", approximately 30,000 subjects (men whowere heavy cigarette smokers and 45 years of ageor older) were enrolled at the Memorial SloanKettering Cancer Center, Mayo Clinic and JohnsHopkins Oncology Center. Although dualscreening with annual CXRs and annual sputumcytology examinations was able to detcct earlystage carcinoma particularly squamous cellcarcinoma98, it was not associated with improvedoverall survival compared with CXR alone lOo, Onereason for this inability to improve survival islikely related to the poor sensitivity of the sputummorphological studies that were available at thattime. Of early lung cancer detected in the NCItrial, less than 10% were detectable only byroutine sputum cytology. The negative findings ofthe NCI trial resulted in a loss of enthusiasm forlung cancer early detection, However, the annualsputum specimens obtained from individualsscreened at]ohns Hopkins were archived and thepatients were monitored for 8 years1OO

• Tockmanet al 101 compared the sputum fr01ll patients whowent on to develop cancer with the sputum frompatients who remained cancer free, Twomonoclonal antibodies were applied to thearchived sputum speciinens and positive stainingpredicted the subsequent development of lungcancer approximately 2 years before clinicalrecognition of the disease, with a sensitivity of91% and a specificity of 88%"'.

524

In the Mayo Lung Cancer Project, subjectsrandomised to undergo screening CXRs andsputum cytology every 4 months for 6 years hadhigher nlullber of cancers detected as stage I andstage II, and higher 5-year survival rates102

,

However, this did not translate into animprovement in mortality from lung cancer, Theshift in stage distribution and 5-year survival isbelieved to reflect lead-time bias, length-biasedsampling and/or overdiagnosis. The probable roleof overdiagnosis, Le" detection of clinicallyinsignificant tumours, and lead-time bias wassupported by the release of data which describedoutcomes after a mean of 20 years of follow-up:patients with lung cancer manifested asignificantly longer lengtll of survival in thescreened group, but no significant differences inlung cancer mortality were observed betweenscreened and unscreened subject populations103

,

The role of low-dose spiral computedtomography of the chest in lung cancerscreening

While the ultimate role of low-radiation-dosespiral CT Clow-dose cD of the chest in screeningfor lung cancer remains to be determined byrand01nised trials with mortality endpoints whichmay take a decade or more to complete, severalreports have documented that this imagingtechnique is more effective than chestradiography in detecting lung cancer at an earlyand potentially curable stage lO4

,105 Spiral CTimaging takes 15 to 30 seconds, allowingcomplete chest imaging in one breath-hold. Theradiation dose associated with low-dose spiral CTscan is equivalent to or less than that associatedwith a mammogram and lesions as small as 2 to 3mIn in size can be detected. In a study by Kanekoet at w, in which 1,369 individuals with at least 20pack-year smoking histories underwent a lowdose CT scan examination, a CXR and a sputumcytology exainination, primaty lung cancer wasdetected on low-dose CT scans in 15 individuals(14 were stage I) while only 4 of these lesions

Med J Malaysia Vol 56 No 4 Dec 2DO 1


were detected on plain CXRs. The Early LungCancer Action Project (ELCAP)'"' screened 1,000asymptomatic smokers with a 10 pack-year ormore smoking history with CXR and low-dose CTscanning. Lung malignancy was detected in 27individuals by low-dose CT scan and in 7 of theseindividuals by CXR. Of the 27 malignant tumoursdetected by low-dose CT scan, 23 (85%) werestage I tumours. Only 4 of the stage I tumourswere detected on CXR, thus, stage I tumours weredetected 6 times more frequently on low-dose CTscans than on CXRs. However, spiral CT alsodetected more nodules which eventually provedbenign (20.6% versus 6.1%). While the ELCAPdata are encouraging, it is premature torecommend low-dose spiral CT scanning as alung cancer screening strategy. until randomisedtriaLs confirm it has a positive impact on lungcancer mortality.

Other new diagnostic technologies

Lam et al 107 introduced autofluorescentbronchoscopy that is capable without the use ofprotoporphyrins of detecting endobronchiallesions of llloderate dysplasia and carcinoma-insitu that may not be visible with standard whitelight bronchoscopy.

PET using FDG is accurate in differentiatingbenign pulmonary nodules from malignantlesions as small as 1 cm with a sensitivity of 83 to100% and a specificity of 80 to 100%108.11°,Although false positive studies of increased FDGactivity in benign lesions such as abscesses>tuberculosis and aspergillomas have beenreported> when no significant FDG activity isobserved, the lesions are invariably benign.Hypermetabolic lesions are considered malignantuntil proven othernrise.

Three-dimensional virtual bronchoscopy is arapidly developing form of virtual reality imagingbased on actual patient data acquired duringspiral CT examination of the chestlll . It allowsnon-invasive visualisation of the bronchial treeby generating simulated endoluminal images.


Among the many possible applications of virtualbronchoscopy is the measurement of the crosssectional area and length of stenosis which maybe difficult to estimate during bronchoscopy.Such quantitative information can be use"ful inplanning endobronchial stent placement> laserphotocoagulation, cryotherapy andbrachytherapy procedures. Secondary areas ofobstruction distal to the primary lesion can beseen at virtual bronchoscopy even if the moreproxhnal lesion cannot be crossed by thebronchoscope. It also allows the relationships ofthe airnray to extrabronchial anatomy to beappreciated.

The role of early detection techniques in lungcancer patients who have undergonesurgical resection

Recurrences after an apparently completeresection may be locoregional, distant or both,and will develop over the next five years inapproximately 20 to 30% of patients with stage Idisease, in 50% of those with stage II, and in 70to 80% of those with stage III disease ll2

• The vastmajority of recurrences are in distant sites. Therecurrence rate decreases with time afterresection, whereas the rate of new primary lungcancer increases with time and can be as high as1 to 2% per year. Even those patients with themost favourable NSCLC, i.e., those with resecteclT1NOMO lesions, are at high risk for developingsecond primary lung cancers, on the order of 2 to3% per year for at least 10 years after initialresection l13• Therefore, early detection techniquesand continued patient surveillance are importantin this group of patients. The histological type ofthe tumour is a determinant of time to recurrenceand survival in patients with resected stage I lungcancer1l4.J15. Cancer recurrences are more frequentand recurrence rates are higher in patients withnon-squamous lung carcinomall6

.

A retrospective evaluation of 130 patients whounderwent a complete resection of NSCI.C andwho were placed into a routine follow-up orsymptom-driven follow-up showed no

525

CONTINUING MEDiCAL EDUCATION

significant difference in disease-free intervaluntil the first detection of recurrenceJJ7• However,the costs associated with the two groups were

significantly different. The authors of that paperconcluded that routine imaging follow-up is ofquestionable benefit.

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MCQs on Recent Advances in Lung Cancer Diagnosis and Treatment

1. The following statements on lung cancer are truea. Cigarette smoking increases the risk of lung cancer in smokers by 13-fold and in passive

smokers by 1.5-foldb. Mutations in the p53 gene have been implicated in the carcinogenesis of lung cancerc. Surgical resection is the treatment of choice for advanced stage non-small cell lung cancerd. Radiotherapy with conventional fractionation is given at doses of 1.8-2.0 Gy per day at

24-hourly intervals, 5 times a weeke. The injury caused by radiotherapy to normal tissue cannot be reduced by

3-dimensional conformational radiotherapy

2. In non-slnall cell lung cancera. Adenocarcinoma is more common in non-smokers than in smokersb. Compared with best supportive care, combination chemotherapy containing

cisplatin improves the median survival for patients with advanced non-small cell lung cancerc. Radiotherapy alone results in improv.ement in survival in metastatic diseased. Chemotherapy does not palliate symptoms in advanced diseasee. Neoadjuvant chemotherapy can be used to down-stage Stage IlIA disease to allow complete

surgical resection

3. In small cell lung cancera. The presence of metastases in the ipsilateral mediastinal lymph nodes is considered an extensive-

stage diseaseb. Survival is not dependent on the stage of disease at the time of diagnosisc. Treatment with chemotherapy is generally not curatived. The overall response to chemotherapy is in the range of 80% to 90%e, The optimal duration of treatment with chemotherapy is eight courses

4. In the treatment of smal! cell lung cancera. Cytotoxic chemotherapy prolongs survival even in extensive diseaseb. Response to single agent chemotherapy is superior to combination chemotherapyc. Single agent chemotherapy with etoposide has no role in patients of advanc€d age or those with

poor performance statusd, The development of recurrent disease less than 3 months after cessation of induction

chemotherapy portends a poor response to salvage chemotherapye. The addition of radiotherapy to the primary tumour site in patients who respond to

chemotherapy does not confer any survival advantage

5. The following statements on screening and early detection of lung cancer are truea. The earlier lung cancer is diagnosed, the better are the patient's chances of survival after treatmentb. By the time lung cancer is visible on chest X-ray, the disease is already in the late stages of its

natural coursec. It has been shown that lung cancer is detected at an earlier stage by screening with chest radiographd. Screening with chest X-ray decreases the overall lung cancer mortality ratee, Compared to chest X-ray, low radiation-dose screening spiral CT has been shown to be more

effective in detecting lung cancer at an early stage

532 Med J Malaysia Val 56 No 4 Dec 2001

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Recent Advances in the Diagnosis and Treatment of Lung Cancer · RECENT ADVANCES IN THE DIAGNOSIS AND TREATMENT OF LUNG CANCER Non-smallcell lung cancer Non-smallcell lung cancer