Complete spontaneous remission in a patient with metastatic non-small-cell lung cancer

Annals of Oncology 8: 1031-1039, 1997. © 1997 Kluwer Academic Publishers. Printed in the Netherlands.

Clinical case Complete spontaneous remission in a patient with metastatic non-small-cell lung cancer Case report, review ofliterature, and discussion of possible biological pathways involved H. Kappauf,1 W. M. Gallmeier,1 P. H.Wiinsch,2 H.-O. Mittelmeier,2 J. Birkmann,1 G. Buschel,1 G. Kaiser1 & J. Kraus3 'Medical Clinic 5/Oncology & Hematology, 2Pathology, Nuremberg City Hospital, Germany; 3Pathologist, Traunstein, Germany

Summary

Spontaneous remission of cancer (SR) is defined as a complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression. We report the case of a 61-year-old man who presented with extensive metatastic disease five months after pneumonectomy for poorly differentiated large cell and polymorphic lung cancer. A vast metastatic tumour mass of the abdominal wall was confirmed histolologically and there was clinical and radiographic evidence of liver and lung metastases. Eight months later, the patient was operated on for a hernia, which had developed in the inguinal biopsy scar and the surgeon

Case report A 61-year-old man with recurrent nuchal pain received a medical check-up including a chest radiograph, which revealed a solitary peripheral lung tumour, confirmed by computed tomography (CT) (Figure 1). The patient was admitted to the Nuremberg Hospital and underwent thoracic surgery on July 23,1990: at thoracotomy a solid mass was found in the interlobarfissure,which infiltrated in equal proportions both lobes of the left lung. In situ biopsy indicated undifferentiated carcinoma. Thus a pneumonectomy was performed, including excision of enlarged central and bifurcational lymph nodes. Histological examination showed a 4 cm sized peripheral, partly necrotic, heterogenous, large cell and and polymorphic cell lung cancer, predominantly a poorly differentiated adenocarcinoma with disseminated squamous cell differentiation, infiltrating the visceral pleura of the upper and lower lobe (Figure 2). A 0.7 cm satellite tumour was found very close to the main tumour mass. None of the 15 hilar lymph nodes and multiple bifurcational lymph nodes showed metastatic infiltration. Fine needle biopsy of an ultrasonically inhomogenous area of the liver showed just fatty liver infiltration. An abdominal CT scan was unremarkable. Thus his disease was

confirmed complete clinical SR of the abdominal wall metastases. Again five months later there was no longer any radiologic evidence of liver and lung metastases. Complete remission has persisted more than five years. Histology of the primary and of the abdominal metastases were reviewed by several independent pathologists. SR is an extremly rare event in lung cancer. This is the first documented case of clinically evident visceral metastases of a bronchiogenic adenocarcinoma developing after complete resection of the primary and then showing complete SR. The epidemiology of SR is reviewed and possible mechanisms involved in SR are discussed. Key words: antiangiogenesis, apoptosis, cell differentiation, lung cancer, spontaneous remission

staged pT2, pNO, G3, MO, R0, and adjuvant treatment was not recommended. In December 1990, whilst on a rehabilitation stay at a spa the patient developed abdominal pain and a nontender mass in the right inguinal region. As an incarcerated hernia could not be excluded, surgical exploration was performed on December 6, 1990. This revealed a vast solid tumour. The surgeon therefore restricted his procedure to an ample biopsy (size of specimen 5 x 4 x 4 cm), which demonstrated infiltration of the abdominal wall by a large cell, mainly undifferentiated carcinoma, corresponding to the primary lung cancer (Figure 3). On January 16, 1991, the patient sought an oncological consultation at the Nuremberg Hospital, reporting weight loss of 5 kg within the preceding month, dysphagia, and lower abdominal pain. His performance status was 2 on the ECOG scale. A firm plaque of tumour was palpable in the right lower abdomen. Laboratory tests were pathological for ESR (45 mm/lh), WBC (13.5/nl), haemoglobin (11.4 g/dl), serum gamma-glutamyl-transpeptidase (G-GT: 96 U/l, normal < 25) and alkaline phospatase (241 U/l, normal <200). An abdominal CTscan (January 18, 1991) showed a 5 x 8 x 10 cm mass of tumour in the abdominal wall completely infiltrating the right rectus muscle and ex-

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1032 ual improvement month by month, regaining his former weight. He had not received any conventional or unconventional oncological treatment and due to his stoic attitude had not touched the prescribed analgetics either. On September 20, 1991, the patient was operated on for a hernia, which had developed in the 1990 inguinal biopsy scar. The surgeon did not find any evidence of the tumour previously seen in the abdominal wall, which he erroneously believed to have been completely resected. Therefore, he did not take a biopsy of the scar tissue. At a check-up on March 2, 1992 the patient's performance status was 0, and there was no longer any evidence of malignancy at physical examination (WMG), chest radiography, and abdominal CT scan (Figure 5). Later Figure 1. CT-scan showing solid peripheral tumour of left lung (July on the patient went back to work and his fine condition 1990). continued when he was seen on June 29,1997. tending from the subcutaneous tissue of the right inguinal region to the peritoneal cavity (Figure 4). The right lobe of the liver now showed a hypodense mass of 10 cm in diameter bossing the caudal liver contour. Moreover, intrapulmonal nodules (1 cm in diameter) were detected by chest radiography and additional fluoroscopy. Faced with this evidence of rapidly progressive pulmonary and abdominal metastatic disease, the oncologist (WMG) talked openly with the patient and his family about the situation and recommended analgesic treatment and supportive home care by the family physician. The oncologist did not receive any news of the patient until September 1991, when he returned in good physical condition. The patient's performance status had continued to deteriorate with a weight loss of another 10 kg till March 1991, when he resigned himself to make his will. Thereafter, however, the patient had experienced a grad-

Definition of spontaneous remission and contextual considerations.

Based on the most commonly accepted definition by Everson and Cole [1, 2] SR refers to a complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or in the presence of therapy which is considered inadequate to produce the resulting regression. Regressions should last at least one month and should exceed waxing and waning of stable disease. This definition of SR is unequivocal for tumour regressions without any medical treatment or after treatment failure. However, in some cases it may be quite difficult to distinguish between treatment-induced remission and spontaneous remis-

Figure 2. Histopathological slide of primary tumour: predominantly poorly differentiated Adenocarcinoma (PAS-staining, magnification 240, July 1990).

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1033 •f

-

Figure 3. Histopathological slide of solid mass of abdominal wall: poorly differentiated, pleomorphic carcinoma with giant cells (HE-staining, magnification 375, December 1990).

sion coincidental to inadequate therapy. For the term ispontaneousi remission touches epistemological issues concerning causative attribution and definition of therapy.

Throughout the history of medicine there have been sporadic reports of cancer regression, which nowadays would be refered to as SR - the alleged miraculous cure of a painful cancer of the foot near the end of the 13th century made that former patient later known as St. Peregrinus, patron saint of patients with cancer [3]. Since histopathological examination became a prerequisite for a malignant diagnosis at the end of last century, SR has

been widely documented in the medical literature. There has been both an increase in number and of the sophistication of scrutiny of reported cases in the last two decades. Case numbers in the few reviews of the medical literature on SR vary considerably, partly due to different inclusion criteria concerning definition, tumour entities and rigidity of required documentation. Everson and Cole reported 176 cases of SR from 1900 to 1964 [1] and added six cases later. Challis and Stam updated that review and included SR of leukaemia, lymphoma and retinoblastoma. They claimed 489 case studies of SR of malignant disesases from 1900 to 1987 but did not present detailed patient information [4]. O'Regan and Hirshberg [3] extensively searched the world's medical literature for SR and selected 1051 cancer references and 216 elaborated case reports for their annotated bibliog-

Figure 4. Abdominal CT showing solid mass in right inguinal region infiltrating abdominal wall (January 18, 1991). Courtesy of Dr. Simon, Nuremberg.

Figure 5. Abdominal CT showing relapse of hernia in right inguinal region, no more evidence of solid tumour (March 1992). Courtesy of Dr. Simon, Nuremberg.

Epidemiology of spontaneous remission in cancer

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1034 raphy using the definition of Everson and Cole as a standard. Doubtlessly case studies in the literature do no reflect the true incidence of SR [5]. Cole [2] estimated SR to occur in 1 of 60,000 to 100,000 people with cancer. SR thus represents a rare phenomenon, which is seen sporadically in every type of cancer. However, nearly two thirds of all SR apparently occur in just a few types of malignancies: malignant melanoma, renal cell cancer, low-grade non-Hodgkins's lymphoma (NHL), chronic lymphocytic leukaemia (CLL) and neuroblastoma in children. Older reviews also describe a substantial number of SR in soft tissue sarcomas and choriocarcinomas [3]. The frequency of SR in metastatic malignant melanoma is reported to be between 0.22 and 0.27%, whereas the incidence of metastatic melanoma with an completely regressed or an inapparent primary ranges from 3.7% to 15% [6, 7]. Frequency of SR of metastasis in renal cell carcinoma following nephrectomy has been estimated between 0.3% and 4%, and lung metastases were involved in 90% of the cases [8-11]. In low-grade NHL/CLL SR, mostly temporary, occurs in 9% to 23% [12-15], more freqently in follicular small cleaved NHL (30%) than in CLL (1.0-1.8%). Some 10% of the children with neuroblastoma present with stage IVS and they experience spontaneous resolution of their metastatic disease very regularily [16, 17] if they do not succumb to prior mechanical complications of bulky disease. Incidence of SR in infants with localized neuroblastomas is about 2%, but screening data suggest a distinctly higher regression rate at the preclinical stage [18, 19]. There are few cases of SR of high grade NHL [20-22] and chronic myelogenous leukaemia (CML) [23]. The same applies to acute leukaemia, for which SR was first reported in 1878, the disease evolving with fatal infection [24-28]. SR is extremely rare in lung cancer. In spite of its global high incidence, Everson and Cole [1] reported only two cases, Lowy [29] had only found 4 previous cases in the medical literature up to 1984, when he reported an additional case of SR in a patient with metastatic small cell lung cancer. Challis and Stam [4] refered to 25 cases, whereas O'Regan and Hirshberg [3] accepted eight case reports only. We have reviewed the case reports and lung cancer references of O'Regan and Hirshberg's annotated bibliography. A Cancerlit search up-dated the SR references to 1997 and we did not find a more recent report of SR in lung cancer. Thus, we added 10 sufficiently documented cases of SR of bronchiogenic carcinoma including our patient to thefivecases reported by Lowy (Table 1). Our list may be incomplete as we did not include references of SR, when we could not obtain the respective journals and ignored some reports of SR which did not give consistent information about the clinical course and follow-up. The incongruent epidemiology of different types of cancer and SR stimulates the discussion of possible mechanisms involved.

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Mechanisms involved in SR of cancer SR of malignancies apparently is mediated by two basic biological pathways: differentiation of malignant cells to a normal phenotype and/or cell death either by apoptosis or inflammatory necrosis. The physiological pathways leading to cell differentiation or cell death are dovetailed in a complexe way [30] to maintain genome stability and tissue function. The variety of clinical features associated with SR suggests multiple biological mechanisms that may lead to SR. Apoptosis In apoptosis irreversible DNA-fragmentation is mediated by Interleukin-1 -converting enzyme(ICE)-like proteases. This process is positively or negatively regulated by p53, bcl-2, 6c/-homologues, ceramid, WAF, BAX and the CD95 (APO-l)/CD95-ligand system [30, 31]. Malignant tumours grow less by proliferation than by loss of apoptosis. Apoptotic cell death appears to play a more important role in tumour dormancy than arrest of proliferation [32]. Kaufmann et al. [33] demonstrated the role of intrinsically activated apoptosis in a patient with leukaemic biclonal mantle-cell lymphoma and 15 recurrent cycles of exacerbation and spontaneous remission over a period of 50 months. Nagel et al. [34] recently reported a case of a B-cell-NHL showing a quite similiar clinical course with recurrent SR, finally evolving into B-CLL after 10 years. An extensive case report by Hornstein and Miilke [35] on SR of IVS neuroblastoma in a newborn may reveal important insights: after initial tumour progression they witnessed slow SR within six months. They repeatedly biopsied the multiple skin nodes and did not find any signs of maturation histopathologically but a more and more 'regressive' transformation apparently consistent with apoptosis - this term had not yet been coined in 1960. Apoptotic cell death has also been shown by another group to be associated with favourable outcome in childhood neuroblastoma [36].

Immunological and cytokine mechanisms Local cytokine release and cellular immune activation resulting in inflammatory necrosis or T-cell mediated apoptosis may explain reports of SR following severe local infection. This applies to case 4 and 6 of Table 1 and a number of Everson and Coles case studies [2]. Cancer treatment by 'Coley's toxins' starting at the end of last century was based on the same type of observation: regression of cancer in the presence of infection, mainly erysipelas. Over 1200 advanced cancer patients were treated with 'Coley's toxins' and complete remission rate was 22% including 30 patients reported to be cured. Anti-tumour activity was mainly observed in tumours of mesenchymal origin and has been revaluated

1035 Table I. Sr in lung cancer. Review of literature. SR duration (year)

No.

Author

Year

Age/sex

Histologic features

1

Blades and McCorkle

1954

59/m

Squamouscell

Boyd

1966

56/m

Adenocarcinoma

3

Terry and Roger (in Boyd)

1966

77/m

Anaplastic carcinoma

12

4

Margolis and West

1967

58/m

Adenocarcinoma

12+

5

Emerson et al.

1968

63/m

Squamous cell

12

6

Bell

1970

37/m

Squamous cell G3

10+

7

Smith

1971

59/m

Squamous cell

15

8

56/m

Oat and squamous

9

43/m

Squamous cell

Inoperable tumor at thoracotomy, postoperative fever, SR within six months. A new lesion appeared in the contralateral lung with skull metastasis five years later. Patient died without autopsy' permission Malignant pleural effusion which cleared after multiple thoracocemeses: No parenchymateous disease was seen by X-ray. Death of terminal pneumonia after a CVA 3.5 years later. Autopsy showed dense fibrous tissue with beds of inactive-looking adenocarcinoma Nine years later the mass in the hilum was no longer seen. Death 12 years later of metastatic pancreatic carcinoma which showed no resemblance to the original pathologic finding Segment resection, seven months later pneumonectomy, not considered as R0 Following pneumonectomy thoracic empyema for eight years before clinical improvement Tumor inoperable at thoracotomy. Death of pancreatic cancer 12 years later without any residual bronchogenic cancer at autopsy Tumor inoperable at thoracotomy, thus irradiation, but only 1200 R applied without any radiographic response Two weeks of postoperative fever. Five and a half months later normal chest X-ray Excellent health 10 years later Left pneumonectomy with residual non-rcsectable tumour on atnum no evidence of malignancy' at autopsy 15 years later Left pneumonectomy, residual non-resectable tumour encircling incised atnum No evidence of malignancy at autopsy seven years later Right pneumonectomy with non-resectable residual tumour encircling incised atrium. Patient was alive 11 years later and assumed to be cured Tumor was biopsied bronchoscopically and classified cTl cNO M0. Patient refused specific therapy. No evidence of malignacy four years later by chest X-ray and bronchoscopy Chest X-ray showed definite mass above the right hilus, extending from the level of the aortic knob up to the clavicle. Right scalene node biopsy lead to diagnosis of metastatic small-cell carcinoma No specific therapy was recommended to the minimally symptomatic patient. Chest X-ray was reported as negative six months later Twelve years later coronary bypass surgery without evidence of carcinoma Thoracotomy with needle biopsy of left hilar mass revealed squamous cell carcinoma Needle biopsy of left adrenal gland (CT showed 6 cm mass) revealed malignant cells compatible with metastatic squamous cell carcinoma. No specific therapy. Gradual decrease of hilar mass in follow up. Negative CT of chest and abdomen after two years Bronchoscopic biopsy and biopsy of inguinal lymph node lead to diagnosis of metastatic small-cell carcinoma. Further diagnosis of cirrhosis of liver. Negative X-ray and bronchoscopy six weeks later. After six years death of newly evolved hepatocellular carcinoma Evidence of bone metastasis in bone scan and abdominal CT three months following a lobectomy for adenocarcinoma. Patient declined chemotherapy Negative bone scan one year later After eight years again positive bone scan and biopsy confirmed metastatic adenocarcinoma

3.5

7 11 +

10

Depierrc et al

1984

57/m

Squamous cell G2

11

Lowy and Enckson

1986

55/m

Oat cell G3

12

Sperduto et al.

1988

61/m

Squamouscell

13

Nakanoetal.

1988

50/m

Small cell G3

14

Papac

1990

62/f

Adenocarcinoma

8

15

Kappaufetal.

1997

61/m

Adenocarcinoma/ squamous cell

5.5+

4+

19+

2+

with present knowledge of tumour necrosis factors which proved inactive as a single agent in clinical trials - and other cytokine effects [37, 38]. Postoperative empyema has been in some reports associated with better survival in resected lung cancer [39]. Rosenberg's pioneering studies of modern oncological immunotherapy have been encouraged by his observation of a long-term spontaneous regression of hepatic metastases from gastric carcinoma [40] after streptococcal peritonitis. Cytokines are released in viral infections and there are quite a number of SR, closely related to infections like measles, viral hepatitis, herpes zoster or chickenpox [12-15]. Sporadic anti-tumour effects of BCG-therapy and other immunostimulatory agents or mutagens in patients with metastatic melanoma argue in favour that immunoreac-

Patient course

Four months after R0 pneumonectomy extensive metastatic disease confirmed by biopsy of abdominal mass which had disappeared eight months later. Persisting complete remission 5.5 years thereafter

tivity may be involved in SR [41]. Anti-idiotypic antibodies have been proposed as causal agents in SR [12], because they can ocasionally be found in blood of cancer patients. Recently, natural IgM-antibodies against neuroblastoma cells were detected in about 80% of normal children and adolescents but not in young neuroblastoma patients [42]. SR of AML has been reported after severe pneumonia [27] or another infection and multiple leucocyte transfusions [25]. Moreover, some lymphoproliferative disorders developing during immunosuppressive therapy have regressed on stopping the immunosuppression [43]. The role of cellular immune factors in tumour control is also underscored by the observation that patients with acute or chronic myelogenous leucaemia relapsing after allogenous BMT may reach a remission

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1036 following the transfusion of donor buffy coat. This graft versus leukaemia effect is mediated by CD4+-lymphocytes [44]. But SR was also observed in patients with HIV-compromised T-cell immunity with a case report of SR in AIDS-related high-grade malignant lymphoma and concurrent progression of the underlying disease to death [45, 20].

Differentiation mechanisms SR of childhood neuroblastoma by regression and maturation to benign ganglioneurinoma is well known [18, 46, 35]. A differentiation mechanism has also been observed in retinoblastoma, adrenocortical carcinoma, teratocarcinoma and gestational choriocarcinoma [47]. Differentiation mechanisms may be involved in the reversal of early stage carcinogenesis after cessation of exogenous carcinogens. The majority of gastric Maltlymphomas disappear after helicobacter pylori eradication. Everson and Cole noted that in 12 of 13 of their SRs of bladder cancer regession occured after transplantation of the ureter into the colon and they presumed diversion of a carcinogenic agent together with the urine [2]. Preinvasive cancers of the bronchial epithelium of heavy smokers may regress if the person stops smoking. Premalignant lesions of the cervix and the mouth may also disappear if irritant factors are removed [47].

product of plasminogen, can cause human carcinoma to regress to a tiny nodule in a dormant state denned by a balance of apoptosis and proliferation of the tumour cells. Extrinsic angiogenesis inhibitors might explain the sporadic observation of SR evolving after transfusion of blood products. There is some experimental evidence that a primary rumour may produce negative regulators of angiogenesis and resection of the primary thus may lead to growth of hitherto dormant micrometastases [32, 50]. bFGF correlates with bad prognosis in renal cell cancer. On the other hand primary melanomas may actually completely regress at the time of neovascularisation, probably due to the inhibitory effect of endothelium derived IL-6 or cell-mediated immunity [6, 50]. The heterogenity of angiogenic phenotype in a tumour and the dependency of angiogenic regulation from microenvironmental factors might explain why incomplete resection of the primary or of metastases may favorably change the angiogenic properties of the residual tumour and in rare cases result in further spontaneous remission. Smith [51] reported three patients with incompletely resected lung cancer who apparently underwent SR of their residual atrial tumours (Table 1). Regression to dormancy may explain some temporary SRs. In three cases of SR of Table 1 dormancy was evident clinically or histopathologically.

Telomerasc inhibition

In 176 cases of SR reported by Everson and Cole, 20 regressions may have had a hormonal background [2]. For example, three melanomas and metastases from a sarcoma regressed after delivery of a child. SR of breast cancer, which were reported in older reviews and were coincidental to pregnancy, partuition or menopause, are perhaps not so enigmatic with today's knowledge of the hormonal influences in this type of cancer. Endocrine changes also may be involved in SR of renal cell cancer, where some reports of endocrine therapy have claimed remission rates of up to 12% [11].

Telomerase activity appears to be repressed in somatic cells and tissues but is reactivated in immortal cells and human cancer. Hiyama et al. [17] demonstrated low or lacking telomerase activity without overexpression of c-myc appeared to be a favorable prognostic factor for regression. They proposed that this subset of neuroblastomas may be formed from remnant neuroblasts and telomerase activity may be insufficient to maintain telomere length. Thus in many IVS neuroblastomas, as well as in some stage I and stage II neuroblastomas, the malignant cells may finally undergo growth arrest and perhaps apoptosis, resulting in spontaneous regression.

Angiogenesis inhibition

Psychoneuroimmunological (PNI) mechanisms

The growth of solid tumours is angiogenesis-dependent and angiogenesis is positively regulated by at least 14 angiogenic proteins. On the other hand, endothelial growth is inhibited by a group of endogenous proteins including thrombospodin, platelet factor 4 (PF4), IL-6, tissue inhibitors of metalloproteinase (TIMP), steroids, proliferin-related protein, endostatin, and angiostatin. Tumour growth may be inhibited in the presence of a mutant endothelium receptor [48]. Some of these endogenous angiogenesis inhibitors are positively regulated by p53, IFN, and IL-12. O'Reilly et al. [49] showed that human angiostatin, a strong anti-angiogenic cleavage

Sensation-seeking reports on putative psychosocial or psychospiritual aspects in SR or long-term survival of cancer and quite a few publications in psychosocial journals ignore the natural course of different types of cancer, their biological prognostic factors and the contribution of state-of-the-art oncological therapy to a favorable outcome [3, 52-54]. Some cases of SR of cancer associated with religiosity or powerful beliefs have been scrupulously documented and cannot be dismissed [55]. It is unclear, however, whether the association of cure with beliefs is causative or coincidental. Powerful beliefs are not frequently an evident trait in patients with SR.

Hormonal mechanisms

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1037 Patients cured of cancer often report gained psychological strength with increased zest for life and a greater appreciation of the commonplace from having faced the stress of cancer and survived [56]. Thus, retrospective interviews of SR patients may be misleading, A causative role of personality traits and behavioural factors in the substantial number of SR in infants seems unlikely. PsychosocTal responses have a definite impact on the quality of life of patients with cancer but explanations of SR which emphasize the patients' personality traits, coping patterns or cognitive efforts are to be cautioned.

Discussion An unusual feature of this case of spontaneous remission of metastatic bronchogenic cancer is its unequivocal documentation: a large metastasis of the the abdominal wall was confirmed by ample surgical biopsy and the histologic slides were reviewed by several pathologists and compared to the histological findings of the primary. Ten months later complete remission of the extensive metastatic tumour of the abdominal wall was macroscopically evident to a different surgeon - who was informed about the malignant disease - when he revised the inguinal excision biopsy scar for herniotomy. Both abdominal CT scans which showed extensive metastatic disease and complete remission were carried out by the same radiologist. There was no episode of febrile infection assotiated with regression nor did the patient receive unconventional cancer treatment. The patient did not use a special cognitive coping style though he received very empathetic support from his wife. SR was preceded by an ample excision biopsy of the metastic abdominal mass. Incomplete resection of this histopathologiclly very heterogenous tumour might have reversed a paracrine imbalance of angiogenic and antiangiogenic mediators. Even without recognition of lung and liver metastases for which there was no biopsy proof, SR of the patient's extensive metastatic abdominal mass constitutes an extraordinary event.

Conclusion SR is a rare but exciting event in oncology and nowadays there is no more doubt on the validity of the observation. Nevertheless, oncological decisions cannot be based on the statistical likelyhood of SR except in favourable stages of infants with neuroblastoma. Temporary SR does not necessarily prolong survival or change the ultimate course of the malignant disease. Neither does SR of a primary cancer prevent secondary malignancies, nor is SR synonymous with good health. However, patients with SR deserve more clinical attention, systematic registry of cases, and sophisticated scrutiny as they present an in vivo model of biological tumour control. Knowledge of the mechanisms involved in such

tumour control may result in new therapeutic approaches in oncology. There is evidence for common biological ultimate pathways in therapy-related regressions and spontaneous remissions. The mode of action of cytotoxic chemotherapy is more by inducing apoptosis than cytotoxic necrosis [31]. Moreover, chemotherapeutic drugs like cyclophosphamide, paclitaxel, doxorubicin, epirubicin, and mitoxantrone demonstrate effective inhibition of angiogenesis [50], and some cytotoxic drugs may induce anti-tumour immunoreactivity [41]. IFN shows anti-proliferative, anti-angiogenic, differentiating, and immunomodulatory effects. Lowy [29] considers cases of SR to be a "vital factor in perpetuating many quackery treatments, whether by 'faith healing', machines, holistic nutrition or placebo drugs". SR is, however, an exciting event, though the same applies to long term tumour dormancy [57, 58] and exceptional treatment related cancer survival - even in extensive disease of small cell lung cancer, l%-2% of the patients survive more than 10 years [59]. Thus, in addition to rigid scrutiny of the rare carefully documented cases of spontaneous remissions, evaluation of the more frequent patients with an exceptionally favorable outcome following conventional oncological therapy and best case analysis of putative cancer regressions by unconventional treatment may help to elucidate the biological mechanisms involved in spontaneous remissions. This report indicates that even advanced cancer may be a reversible process.

Acknowledgement Arbeitsgruppe Biologische Krebstherapie, supported by a grant of Deutsche Krebshilfe, D-Bonn.

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Correspondence to: Dr. H. Kappauf Medizinische Klinik 5 Institut fur Medizinische Onkologie und Hamatologie Klinikum Nord der Stadt NOrnberg D-90340 Nurnberg Germany

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