Download pdf - Cryotherapy in Early Superficial Bronchogenic Carcinoma* · 2017. 6. 3. · bronchogenic carcinoma 5 to 27 months after cryo-therapy. Of these five patients, two patients had a clinical

Cryotherapy in Early SuperficialBronchogenic Carcinoma*Nadine Deygas, MD; Marios Froudarakis, MD, FCCP; Gervais Ozenne, MD;and Jean-Michel Vergnon, MD, PhD

Background: Treatment of early superficial bronchogenic carcinoma (ESBC) is under debate, andno consensus has been achieved. Different therapeutic methods have been proposed, includingsurgical resection and endoscopic methods.Study objective: To assess the efficacy of cryotherapy in patients with ESBC.Patients and methods: Patients included in the study had histologically proven ESBC afterfiberoptic bronchoscopy. Cryotherapy was performed through a rigid bronchoscope. Efficacy wasassessed by endoscopy with multiple biopsies 1 month after treatment and during the follow-upperiod. Parameters studied were response to treatment, adverse effects, and survival.Results: We included 35 patients (34 men and 1 woman). The mean age was 61 6 9 years. Multiplelocations of ESBC were observed in seven patients (20%). Complete response rate at both 1month and 1 year was 91% (32 patients). No severe adverse effects were noted. Local recurrencewas observed within 4 years in 10 patients (28%). A follow-up period of at least 4 years wasavailable in 22 patients; of them, 11 patients (50%) were long-term survivors.Conclusion: Our results suggest that cryotherapy is an effective method of treatment in patientswith ESBC. Due to its relative tolerance compared to surgery, cryotherapy could be proposed asa first-line therapy in this population with high carcinogenic risk.

(CHEST 2001; 120:26–31)

Key words: cryotherapy; curative intent; early superficial cancer; lung cancer; therapeutic endoscopy

Abbreviations: CIS 5 carcinoma in situ; ESBC 5 early superficial bronchial carcinoma; FB 5 flexible bronchoscopy;PDT 5 photodynamic therapy

L ung cancer mortality has remained unchangedover the years.1,2 Most patients die from distant

metastasis, despite aggressive therapy. In broncho-genic carcinoma in situ (CIS), the tumor is limited to

For editorial comment see page 3

the epithelium without rupture of the basementmembrane.3 When the basement membrane is notintact, the lesion is still considered CIS if there is noinvasion of the lamina propria.3,4 These lesions,called early superficial bronchogenic carcinoma(ESBC), are multifocal in about 15% of patients2,5

and are incapable of metastasis.3,4 However, their

recurrence after surgical treatment is frequent, sincesubsequent primary tumors develop in about 5% ofpatients each year.5

Opinions concerning the management of ESBCare not unanimous, and few reports deal with theselesions.4 In the past, therapeutic options had beenlimited to surgical resection. As surgical resectionfailed to avoid development of another primitivelung cancer, endoscopic therapies such as photo-dynamic therapy (PDT) were tested.6 –9 Cryother-apy is one of these conservative therapies, while ithas been never tested as a primary treatment ofthese tumors. Its effects result from the selectivecellular necrosis due to tissue freezing and theelimination of their vascularization. This is an inex-pensive and safe method, but the results are some-what delayed. Nitrous oxide-driven cryoprobes aremost often used. Cooling is due to the JouleThompson effect.10 –13 The aim of this study was toevaluate the efficacy of such a cryotherapy used asthe unique treatment in patients with ESBC.14

The parameters studied were tolerance, responseto treatment at 1 year, disease-free interval, andoverall survival.

*From the Service de pneumologie et d’oncologie thoracique (Drs.Deygas, Froudarakis, and Vergnon), Hopital Nord, Saint-Etienne;and Centre medico chirurgical du cedre (Dr. Ozenne), Bois-Guillaume, France.Manuscript received December 16, 1999; revision acceptedJanuary 31, 2001.Correspondence to: Jean-Michel Vergnon, MD, PhD, Service depneumologie et d’oncologie thoracique, Hopital Nord, AvenueAlbert Raimond, 42055 Saint-Etienne Cedex 2, France; e-mail:[email protected]

26 Clinical Investigations

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Materials and Methods

Patient Selection Criteria

All patients with an exclusive diagnosis of ESBC detected byconventional white-light flexible bronchoscopy (FB) were eligiblefor the protocol. These lesions presented as irregular and well-limited zones of thickening. The ESBC features defined oncriteria previously described3,4 were further proven on multiplebiopsies, with negative radiographic and CT scans findings. Afterinformed consent, these patients underwent cryotherapy alone(even when operable).

Population

Thirty-five patients (34 men and 1 woman) with 41 lesions (Fig1) were enrolled in this study between March 1985 and April1997. Inclusions were stopped after this date in order to obtain asufficient follow-up duration. These patients were treated in 10different French centers: Saint Etienne (16 patients), Strasbourg(5 patients), Rouen (4 patients), Grenoble (3 patients), Tours (2patients), Bordeaux (1 patient), Chevilly-Larue (1 patient),Dieppe (1 patient), Nimes (1 patient), and Orleans (1 patient).

About one half of the lesions were discovered at systematic FBcheckups, and the others were found after various complaints,including hemoptysis, cough, and sputum. Seven patients (20%)had two or more lesions. The locations of the different lesions arepresented in Figure 1. These lesions were histologically definedas typical CIS in 27 patients, and were considered as CIS in abroad sense in the other 8 patients because the basementmembrane was not intact, although without invasion of thelamina propria.3,4

The mean patient age was 61 6 9 years (range, 33 to 80 years).All patients were smokers, and 14 of them had COPD. Most ofthe patients (42%) had a clinical history of bronchogenic (sevenpatients) or upper aerodigestive tract carcinomas (eight patients)treated previously by surgery or radiotherapy.

Methods

DATE (LP 500; La Motte d’Aveillans, France) or ERBE(ERBOCRYO CA; Tubingen, Germany) equipment was used. Incase of a central location of the tumor, rigid cryoprobes wereemployed, while flexible probes were used for peripheral loca-tions. Both nitrous oxide-driven cryoprobes were introducedthrough a rigid bronchoscope under general anesthesia. Rigidcryoprobes were utilized for 19 patients (54%), flexible cryo-probes for 7 patients (20%), and both rigid and flexible cryo-probes for the last 9 patients (26%). Treatment of lesions wasperformed according to the method described earlier.13 Briefly,three cycles of freezing and thawing are performed in each point.Each freezing period lasts about 20 s. All the tumor surface anda marginal area of 5 mm of normal mucosa around the tumorwere treated. The distance between two adjacent applications ofthe cryoprobe is about 5 mm. In these infiltrative lesions, oftenlocated on a carina, the probe is applied laterally on each side ofthat carina, and then the tip of the probe is applied along thecarina crest itself. Ten to 15 days after the first cryotherapysession, an endoscopic control was performed to evaluate mac-roscopically residual lesions in order to perform a second sessionif necessary (in 12 patients) as well as to extract the necroticslough.

Evaluation of Response and Follow-up

Follow-up was performed using radiography and FB withmultiple biopsies at the site treated with cryotherapy at 1, 3, 6,and 12 months, and then every year. Biopsies were performed ofall other lesions detected during endoscopic controls.

Statistical Analysis

Student’s t test was used to compare the mean values of thevariables of the groups studied. Survival was studied from thedate of diagnosis to the last date of contact, using the Kaplan-Meier product limit estimation with log-rank test. A p value of# 0.05 was considered significant for all tests. Statistical analysiswas performed with StatView 4.5 software (SPSS; Chicago, IL).

Results

Tolerance

Tolerance to cryotherapy was judged excellent.There was neither hemoptysis nor bronchial wallperforation. There were no severe adverse effectsdue to general anesthesia. We did observe transientfever following cryotherapy in the first patients; thiswas prevented later by preventive corticosteroidadministration. Necrotic slough never caused signif-icant cough or dyspnea as is sometimes observedwhen cryotherapy is used as a debulking method.13

Local Tumor Control

Results were available for all patients at 1 monthand at 1 year. A complete histologic response wasobtained in 32 of 35 patients at 1 month (91%) andlasted a full year. One of three patients with aresidual lesion at 1 month died in the sixth month ofa metastatic disease. This patient had a clinical

Figure 1. The 41 lesions were treated by cryotherapy alone,throughout a rigid bronchoscope, with rigid cryoprobes wheneverpossible, or with flexible ones especially in upper lobes.

CHEST / 120 / 1 / JULY, 2001 27


history of lobectomy and underwent radiotherapy forcarcinoma 15 months earlier. The two other patientswere administered a second treatment with cryother-apy on lesions that were still in situ, with a survival of36 months and 50 months, respectively.

Seven other patients presented with a local recur-rence after the 12-month evaluation; a total of 10patients (28%) had recurrence. The disease-freeinterval of these seven patients ranged from 13 to 45months. The median overall survival of these pa-tients was 37 months, ranging from 19 to 50 months.These recurrences presented as an invasive carci-noma in six patients and as a CIS in one patient. Thislast patient was treated again using cryotherapy, withan overall survival of 50 months. The invasive carci-nomas were treated with surgery in three patientsand with radiotherapy in two patients; the last pa-tient had respiratory insufficiency and could notundergo any salvage treatment. Method failures areshown in Figure 2.

Second Carcinoma

A second carcinoma was diagnosed in eight pa-tients (23%), 5 to 46 months after cryotherapy,although the effectiveness of the treatment wasproved. Of these patients, three were treated withcryotherapy again, obtaining a complete response

and a survival ranging from 15 to 89 months. Theremaining five patients presented with an invasivebronchogenic carcinoma 5 to 27 months after cryo-therapy. Of these five patients, two patients had aclinical history of pulmonary resection for carcinomaand one patient had been treated a few monthsearlier for a larynx carcinoma.

Longer Follow-up

A 2-year follow-up was available in 32 patients.Twenty of these 32 patients (62.5%) were still alive atthis time. For 22 patients, a follow-up period of atleast 4 years (48 to 89 months) was available. Ofthese 22 patients, 11 patients (50%) were still aliveand were considered as long-term survivors.

At the time of assessment, 19 of 35 patients weredead; 13 patients died of carcinoma (all of themsquamous cell invasive carcinoma), and the remain-ing 6 patients died of an unrelated cause. Of the 13patients who died of bronchogenic invasive carci-noma, only 6 patients died of a recurrence of thecancer on the site initially treated with cryotherapy.The seven other patients developed a second cancerat another site.

Overall median survival and overall median dis-ease-free survival are shown in Figures 3, 4. Theeight patients with CIS in a broad sense exhibited

Figure 2. Graphic representation of complete responses and cryotherapy failures in study patients.



the same course as the whole group, with a disease-free interval ranging from 21 to 53 months (notsignificant).

Discussion

The outcome of bronchogenic CIS is now clearlydemonstrated as unfavorable, with progression toinvasive carcinoma.15 This is confirmed by our re-sults, since six of our seven recurrences were invasivelesions; therefore, ESBC must be treated aggres-sively.

The choice of therapy for ESBC is under debate.4Surgical resection remains frequently recom-mended, while reports published are limited,present contradictory data, and include few pa-tients.16–18 When the surgery concerns more thanone lobe, the associated parenchymal amputationlimits the therapeutic options in case of recur-rence.4,16–18 However, limited resections, such assegmentectomy or sleeve resection, have never beenevaluated in these lesions. The 5-year overall survivalfor surgery has ranged from 50 to 91%,17,18 and wasonly about 10% at 10 years in one of these reports.17

Moreover, several characteristics of this populationwith early stage lung cancers limit surgical efficacy:(1) at the time of diagnosis, these lesions are oftenmultifocal (19% in our population); (2) later, theappearance of a second location in the follow-up isvery frequent17 and reached 23% in our population;(3) functional impairment with severe COPD, com-mon in such heavy smokers, as well as a history ofbronchogenic or upper aerodigestive tract carcinoma(42% in our population) either contraindicate sur-gery or increase mortality. For example, in onesurgical report,18 operative mortality rate was 5 to6%, which is quite high.

Endoscopic methods such as PDT,19–25 laser ther-apy,26 and electrocautery27 would now appear to bemore appropriate in patients with ESBC. A compar-ison to surgery and between endoscopic methods isdifficult, however, due to the lack of randomizedstudies. And, to our knowledge, no prior report inthe literature has studied ESBC patients treated withcryotherapy.14

Efficacy, tolerance, and cost analysis are needed tocompare these endoscopic methods. In terms ofefficacy and tolerance, cryotherapy provided a com-plete response at 1 month in 91% of our patients,and lasted for 1 year without any side effects. Weobtained overall survival rates of 62.5% at 2 yearsand 50% at 4 years. The excellent tolerance tocryotherapy is underlined in all reports due to theselective cytotoxic action of cold, as it avoids collagendamage.11–13 The depth of the cytotoxic action ofcryotherapy in the bronchial wall is . 3 mm,13 whichis sufficient to cure early stage lung cancers.3–5 PDTresults are similar, with complete response ratesreaching 80 to 90%,20,23,24 and local recurrence ratesfrom 10 to 31%.20,24,25 With PDT, long-term survi-vors have also been reported.20–25 However, sideeffects are more frequent and include severe orprolonged cutaneous photosensitization.19–25

Cavaliere et al26 successfully used Nd-YAG lasertherapy in this indication in only 19 bronchogenicCIS selected from 1,585 malignant lesions. Due tothe unselective action on the bronchial wall and thedeep action of Nd-YAG laser, this method can alsolead to severe complications, such as hemorrhage orperforation, especially in untrained hands.

Bronchoscopic electrocautery using soft coagula-tion has been evaluated27 in 13 patients withT1N0M0 lesions with a complete response rate of80%, but with a median follow-up limited to 22months. Side effects of electrocautery are limited forthis indication. However, electrocautery is not as safeas cryotherapy for the bronchial wall: of the 13patients treated, bronchial stenosis scars were de-scribed in 2 patients. Also, necrosis of the cartilagearches has been reported in humans after a 3- to 5-s

Figure 4. Overall survival graph (estimated by Kaplan-Meiermethod).

Figure 3. Disease-free survival graph (estimated by Kaplan-Meier method).

CHEST / 120 / 1 / JULY, 2001 29


application in soft coagulation mode28; in animals, asevere stenosis is always obtained in case of circum-ferential application.29

High-dose rate brachytherapy has been evaluatedfor limited lesions, but not specifically in broncho-genic CIS.30–32 This method produces severe ad-verse events, such as severe hemoptysis, fistula for-mation, and bronchial stenosis,30,31 and seems to bemore appropriate for tumors infiltrating the entirebronchial wall and the peribronchial tissues.9,31

The cost of each method must be taken into account,including devices and consumables. A cryotherapy unitwith rigid cryoprobes is a very inexpensive device,about $8,000, which is less than electrocautery devic-es.13,33,34 Moreover, electrocautery requires a specialinsulated fiberoptic bronchoscope. These low costscontrast with the Nd-YAG laser unit (. $100,000) orwith the very expensive devices for high-dose ratebrachytherapy or PDT, which need two simultaneouslasers plus the cost of photosensitizers.

Conclusion

For ESBC, we think that conservative therapycould be proposed as first-line treatment, sparingthe pulmonary parenchyma and allowing surgicalsalvage when necessary. A frequent endoscopiccontrol is recommended to detect recurrence orother locations. Based first on the efficacy-tolerance ratio and then on the favorable cost ofeach method, we suggest that cryotherapy should bethe best first choice. Randomized trials with long-term follow-up are needed to compare results ofcryotherapy to those of surgery as well as otherendoscopic methods in ESBC, even if patients arecandidates for resection.

ACKNOWLEDGMENT: We thank A. Vandevenne, H. DeCamproger, F. Blanc Jouvan, M. Taulelle, J. P. Homasson, A.Roullier, G. Courty, M. Lavandier, N. Tolstuchow, all membersof groupe d’etude de cryochirurgie, who included patients in thisstudy, and J. C. Barthelemy for revision of this article.

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