Spontaneous Regression of Metastases of Renal Cancer:
`
`A Report of Two Cases Including the First Recorded Regression Following
`Irradiation of a Dominant Metastasis and Review of the World Literature
`
`D. J. FAIRLAMB, MB, DMRT, FRCR
`
`Two cases of spontaneous regression of lung metastases are presented. One is the first report of re-
`gression of metastases after irradiation of a dominant metastasis. The world literature is reviewed, and
`67 documented cases have been found including the two now reported. Attention is drawn to the use of
`immunotherapy in the treatment of advanced renal cancer.
`Cancer 47:2102-2106, 1981.
`
`S event. In a review of the world literature from
`
`POM A N E O U S REc;RFssioK OF I UMORS is a rare
`
`1900- 1966, Everson and Cole" found only 176 cases.
`The tumors most commonly exhibiting this phenom-
`enon were hypernephroma (3 1 ), neuroblastoma (29).
`malignant melanoma (191, and chorioncarcinoma ( 19).
`Complete tumor disappearance in these patients was
`not always seen, and the duration of "remissions" was
`variable: over five years, 40%: two t o five years, 23% ;
`one to two years, 17%: and less than one year, 20%.
`In subsequent analysis of the same patients, Cole8 re-
`corded only three cases of spontaneous regression of
`other metastases following irradiation of a metas-
`tumors were choriocarcinomata, and the
`tasis-two
`other was a malignant melanoma.
`
`nbnormality. Her anemia rcsponded to oral administration of
`iron on both occasions.
`In March 1975, she was admitted for further investigation,
`since her symptoms and anemia had recurred. On this oc-
`casion. clinical examination revealed a left-sided, abdominal
`mass and a painless mass in the left groin measuring 7
`cm x 4 cm. Hemoglobin level was 7.6 g/dl: ESR was 100
`mmihr; electrolytes and liver function tests showed no ab-
`normality: a chest x-ray showed hilar enlargement and small
`pulmonary secondary deposits: and an IVP revealed a mass
`arising from the lower pole of the left kidney, and destruction
`of the left inferior pubic ramus was seen on a pelvic x-ray.
`Tumor circulation corresponding to the groin mass and to the
`area of pubic bone destruction was shown by femoral
`arteriography .
`A left nephrectomy was performed in May 1975, and the
`histology was that of a clear cell carcinoma of the kidney. She
`made an uneventful recovery, but when reviewed a month
`later, the groin mass measured 9 cm x 6 cm and was painful.
`Chest x-ray showed progression of the pulmonary metastases.
`The groin m a s was irradiated by cobalt teletherapy with
`opposed fields receiving 40 Gy (4000 rads) in 15 fractions over
`30 days. N o further treatment was given since she was
`asymptomatic. Successive chest x-rays showed resolution
`and eventual disappearance of the pulmonary deposits by
`August 1976. She remained well until October 1979 when she
`was found to have a solitary posteriorly sited cerebral
`secondary deposit. which, despite her age, has been success-
`fully removed surgically. At the time of writing, there is no
`evidence of any metastatic disease.
`
`C'trsr 2
`In August 1973, a 53-year-old man had had a four-month
`history of hematuria and passing clotspur ureflirmz. Clinical
`examination revealed a left-sided abdominal mass, which
`appeared to be a neoplasm of the kidney on IVP. At the
`apex of the left lung, a preoperative chest x-ray showed a
`
`Case Reports
`
`I
`C'rl.\c,
`A 73-year-old woman was diagnosed as having a clear
`cell carcinoma of the left kidney in April 1975. She had
`complained of general malaise and loss of weight for three
`years: during that time she had been examined twice but had
`not had intravenous pyelography (IVP). There were no
`clinical abnormalities, and investigations revealed iron de-
`ficiency anemia, low serum iron, and a sedimentation rate
`(ESR) of 87 mm per hour. A chest x-ray showed no
`
`From the Deparlments of Radiotherapy and Oncology: Churchill
`Hospital. Headington. Oxford and the Royal Free Hospital, Pond
`Street. London NW3.
`Present address: The Royal Hospital. Wolkerhampton. West
`Midland\. England.
`The ziurhor thanks Dr. E. Hoesen and Mr. P. Powley for their
`advice and for their permission t o report on patients under their care.
`The author also thanks Dr. J . V . Clark for reviewing the histology
`of Case I and Mrs. C. Barnes for manuscript preparation.
`Accepted for publication April 29. 1980.
`
`0008-S43X/8110415/Zl0Z $0.80 L' American Cancer Society
`2 102
`
`Breckenridge Exhibit 1135
`Breckenridge v. Novartis IPR2017-01592
`Fairlamb
`
`

`

`No. 8
`
`REGRESSION OF RENAL METASTASES . Fuirlonih
`
`2 I03
`
`shadow. which was radiologically a metastasis. On August
`14, 1973. a large tumor arising from the kidney and receiving
`extensive adventitious blood supply from the surrounding
`structures was removed. Histology showed a carcinoma of
`the kidney, and a paraaortic node removed at operation was
`completely replaced by tumor.
`A chest x-ray one month later was unchanged, but a film
`taken in January 1974 showed no abnormality. The patient
`remained well until February 1975 when he fractured the
`neck of his left femur following a bicycle accident. A chest
`x-ray showed no pulmonary secondaries, but a pathologic
`collapse of the tenth dorsal vertebra was seen. During his
`admission, he coughed up blood, and clinical examination
`revealed a nodule in his left pectoralis major. A biopsy was
`performed and showed metastatic renal cancer. He was dis-
`charged without further treatment and returned to work.
`However. review in January 1976 showed that the hip fracture
`had failed to unite despite the pin and plate, and lytic changes
`at the fracture site were seen. Although asymptomatic, the
`patient underwent a course of palliative cobalt radiotherapy
`to this area--71 Gy (2100 rads) in three fractions over 21
`days. He remained well, although a chest x-ray in August
`1976 showed a metastasis in the right lung.
`By December 1977, right third and fourth cranial nerve
`palsies developed, but no action was taken since he was
`otherwise asymptomatic. However, in September 1978,
`deteriorating mental function and behavioral disturbances
`led to his admission. A CT scan showed a right frontal
`metastasis: his pulmonary disease remained static, and his
`calcium level was normal. He made a spontaneous re-
`covery, but this proved transient, and he was admitted in
`January 1979 for terminal care following a pathologic frac-
`ture of the right neck of his femur. His physical and mental
`condition was poor, and the pathologic fracture was given
`a palliative single shot of 8 Gy (800 rads) ofcobalt teletherapy.
`He died on August 8, 1979.
`
`Discussion
`In the first case report, the bony and pulmonary
`metastases progressed following nephrectomy, and it
`was only after irradiation of the dominant groin
`secondary that any regression occurred. This report is
`the first record of spontaneous regression of metastases
`from a carcinoma of the kidney after irradiation of a
`metastasis.
`Both cases illustrate prolonged survival that may
`follow spontaneous regression of metastases, and this
`is not unusual as can be seen in the cases in Table 1.
`This table comprises those fully documented instances
`of spontaneous regression of metastatic renal cancer
`unrelated to hormone or other therapy. The sites were
`lung. 60, bone, 3, skin. I , liver, I , thigh, I , and in-
`testines, 1. The latter case is most curious since the
`patient, who had undergone nephrectomy for a hyper-
`nephroma and then radiotherapy to the renal bed,
`passed a piece of ”coarse papillous tissue” through the
`rectum after two episodes of intestinal hemorrhage 22
`
`months after the surgery. Histology of the partially
`necrotic mass was hypernephroid cancer. X-rays after
`a barium enema showed no abnormality. He passed two
`further tumors within the month, and histology was
`again confirmed. At a laparotomy performed for pyloric
`obstruction, a benign ulcer was found. and there was no
`in the abdominal
`evidence of metastatic disease
`cavity-this was 7% years after the initial nephrec-
`tomy (Case 5).
`In the cases previously reported. regression has
`usually followed the treatment of the primary by sur-
`gery (57 cases), or irradiation (four cases, nos. 33, 36,
`43, 5 I , followed by nephrectomy in three patients after
`metastases had regressed). Regression of other metas-
`tases has followed nephrectomy and irradiation of the
`dominant secondary (case no. 66), surgical removal of
`a metastasis in the absence of nephrectomy (case no.
`26), and in five cases before nephrectomy (case nos.
`11, 24, 42, 47, 48). Metastases may progress after
`nephrectomy only to regress later, or even appear after
`nephrectomy and spontaneously resolve. The second-
`aries may return in the same or different sites at a later
`date, and the regression appears to be palliative rather
`than curative. The long natural history of renal cancer
`is shown in a series of 443 patients deemed inoperable.
`because of tumor extent or other reasons: the crude
`survival rate at three years was 4.4% and at five years
`1.7%:’:’
`Whether an individual patient who has metastatic
`renal cancer should undergo nephrectomy is controver-
`sial. Several authors reporting single cases of sponta-
`neous regression after nephrectomy have supported
`this policy. Mims et u / . 2 7 described 97 patients with
`extensive renal cancer with metastases (distant in 5‘7
`cases) and saw only one case of spontaneous regres-
`sion of bony deposits. In their series, the five- and ten-
`year survival rates were 14 of 96 and 3 of 96, respec-
`tively. (They excluded a case of spontaneous regres-
`sion since the patient had only been followed for 13
`months, at which time he was still in remission.) How-
`ever, Middleton’5 reports 33 patients with secondaries
`who underwent nephrectomy, and there were no re-
`gressions and no patient survived two years. Johnson
`er ti/. I Y reported 43 cases with no regressions. The latter
`authors concluded that there was increased survival
`only for those patients who had exclusively osseous
`metastases and suggested that nephrectomy is not
`indicated for the asymptomatic patient with visceral
`deposits. The surgical mortality of nephrectomy in the
`presence of distant spread is not high in the series
`quoted: 6 of 97 and 1 of 43. The one patient died in the
`postoperative period of cerebral secondaries.
`Patients who have a solitary resectable secondary
`deposit should have this and the primary tumor re-
`
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`
`

`

`2104
`
`CANCLR April 15 1981
`
`Vol. 47
`
`TABLE 1 . Fully Documented Cases of Spontaneous Regression
`
`Author
`
`Year
`
`Sex
`
`Age
`
`Site of
`metastases
`
`hl
`M
`M
`F
`h4
`M
`M
`F
`M
`M
`M
`M
`M
`F
`M
`M
`M
`M
`M
`F
`M
`F
`M
`M
`M
`M
`F
`M
`F
`M
`M
`M
`M
`M
`M
`M
`M
`F
`M
`M
`M
`M
`!4
`F
`F
`M
`M
`M
`M
`t.'
`M
`M
`M
`M
`t;
`M
`F
`F
`M
`M
`F
`M
`M
`M
`M
`F
`M
`
`)
`
`SY
`62
`,?
`57
`37
`60
`47
`75
`65
`34
`54
`59
`5x
`58
`55
`55
`43
`57
`63
`4x
`70
`64
`61
`41
`59
`56
`58
`49
`57
`56
`72
`56
`5 1
`3x
`69
`51
`47
`47
`5Y
`59
`70
`36
`59
`70
`55
`39
`68
`61
`4s
`58
`76
`53
`64
`67
`52
`49
`59
`49
`53
`71
`59
`55
`65
`51
`73
`55
`
`L
`L
`I.
`1-
`Intestines
`L
`L
`L
`1.
`L
`I.
`L
`L
`I-
`L
`I.
`L
`L
`L
`I.
`I.
`L
`L
`1.
`L
`L
`L
`L
`1.
`L
`L
`L
`L
`Bone
`L
`L
`L
`L
`L
`L
`I >
`L
`I.
`L
`L
`1-
`L
`L
`L
`L
`L
`Skin
`I .
`Thigh
`1-
`Bone
`L
`L
`Bone
`L
`L
`1,iver
`L
`L
`L
`L
`L
`
`Outcome
`
`5 yr. NED
`5/12 NED
`20 yr. NED
`16/12 NED
`7% yr. NED
`4 yr. NED died
`2 yr. N E D
`7 yr. AWD
`2 yr. N E D
`7/12 N E D
`2 yr. DOD
`3 rno. AWD
`3 yr. DOD
`3 yr. DOD
`1 yr. NED
`2Ih yr. DOD
`2 yr. NED
`4 yr. NED died
`2% yr. NED
`15 yr. NED
`19 mo. NED
`15 rno. NED
`18 rno. AWD
`4 rno. DOD
`9 rno. NED
`5 yr. NED died
`7 mo. NED
`8 yr. DOD
`4 yr. NED
`I2 yr. DOD
`3% yr. NED died
`2 yr. DOD
`2 yr. DOD
`I yr. N E D
`18 rno. NED
`2 yr. DOD
`6 yr. N E D
`13 mo. NED
`Y yr. DOD
`I yr. DOD
`13 rno. AWD
`3 yr. DOD
`3 yr. NED
`18 rno. NED
`6 rno. DOD
`? yr. N E D
`8 yr. DOD
`3 yr. AWD
`4 rno. NED
`20 yr. AWD
`4 rno. DOD
`I5 mo. DOD
`I yr. DOD
`6 rno. DOD
`3 yr. DOD
`4 yr. NED
`? I yr. DOD
`3 yr. NED
`10 yr. DOD
`2 yr. DOD
`18 rno. DOD
`4 yr. NED
`4 yr. NED
`12 yr. NED
`21 mo. NED
`4% yr. NED
`6 yr. DOD
`
`L I Lung: NED = no evidence of disease: AWD = alive with
`disease; and DOD 7 died of disease.
`
`Case
`no.
`1
`Burnpus
`Beer
`2
`3
`Mann
`4
`Gliedman "
`Klimpel
`5
`i
`Arcornano oi trl.
`7
`Cibert t't c r l .
`Bobbitt t'/ t r l .
`X
`Hallahan
`Y
`Kessel
`10
`Ljunngren r / ti/.
`I I
`I*junngren ('I r r l .
`I ?
`Buehler ( 1 1 rrl.
`I ?
`14
`Huehler c / ti/.
`I5
`Lageze c / t r l .
`16
`Nicholls and Siddons
`17
`Kolar e / ti/.
`Sarnellas and Marks
`18
`Miller vr t r l .
`19
`Prentiss r ! trl.
`20
`Hultborn
`? I
`22
`Hultborn
`Miyagdwa and Kodama
`23
`24
`Sakula
`Grahstald
`' 5
`26
`Cliffton (cited by Middleton
`27
`Ljunngren & Claes
`Gonick and Jackiw
`28
`Andrews
`2')
`30
`Jenkins
`31
`Miletinskaia'"
`32
`Adolfsson
`33
`Adolfsson
`34
`Mirns ci trl.
`35
`Taddei and Pistoechi."'
`36
`Hudgins and Collins
`37
`Puchetti I '
`Cockett '
`38
`3')
`Cockett
`40
`Markiewitz c'i trl.
`41
`Claret
`trl. "
`42
`Robinson
`43
`Ridings
`44
`Mathias
`45
`Bloom
`46
`Bloom
`47
`Baert and 'l'anghe I
`Meinders' '
`48
`49
`Garfield and Kennedy
`Garfield and Kennedy
`50
`De Georgi
`51
`Braren ('I rrl. -'
`52
`53
`Silber ('I (rl.
`s4
`Kaplan (cited by Holland I " )
`Susrnano (cited by Holland I ")
`55
`56
`Doolittle I
`57
`Freed oi trl. I
`58
`Freed ('I crl. I a
`59
`Freed ('I rrl. I .'
`60
`Boasberg t'r trl. I
`61
`Ihbrow I
`Deweerd t t rrl. I '
`62
`Ludwig ('I t r l . " '
`63
`64
`Rudowski 'Ii
`Mohr and Whitesel'"
`65
`66
`Present series
`67
`Present series
`.i\es 1-3. 5-30, see IJverson and Cole I '_
`C. . .
`Cases 32-34. 36. 40. 42. 43. 45. 46. 49-SI. see Bloom.'
`
`:)
`
`t
`
`1928
`1937
`I948
`1957
`1957
`1958
`1958
`1959
`1959
`1959
`IY59
`I959
`1960
`1960
`1960
`1960
`1961
`1961
`1062
`1962
`1963
`1963
`1 Y63
`I963
`1964
`1964
`1964
`I964
`I Y6.5
`196.5
`1965
`1966
`1 Y66
`1966
`1066
`1966
`I966
`I967
`1967
`I967
`I968
`I969
`1971
`1971
`1971
`1Y71
`1971
`1971
`I972
`197.2
`1 Y7?
`1 974
`1975
`197.5
`1975
`1975
`1976
`1976
`1976
`I976
`I Y77
`1977
`I977
`I978
`1 Y7Y
`1980
`1980
`
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`Fairlamb
`
`

`

`No. 8
`
`REGRESSION OF RENAL METASTASES . Fuirlumh
`
`2105
`
`moved. The survival figures in 59 cases so treated'"
`were 45% at three years and 34% at five years, which
`are essentially the same for patients undergoing
`nephrectomy in the absence of metastases. This finding
`has been confirmed by Skinner et ul.:{' who reported 12
`of 41 patients alive at five years following removal of the
`primary and a solitary secondary tumor.
`Why spontaneous regression occurs is not clear,
`and that this should occur before nephrectomy is an
`enigma. Removal of the primary tumor may reduce
`hormonal, carcinogenic, or antibody blocking sub-
`stances elaborated by the cancer; alternatively, by
`reducing the large amount of tumor antigen, nephrec-
`tomy may allow the host's immune defenses to over-
`come the metastases.
`The evidence seems to favor an immunologic basis
`for the regression." Renal cancer is highly immuno-
`A re-
`genic and cytotoxic serum factors may
`cent study has shown that most patients (94%) with
`renal cancer have circulating, complement-fixing anti-
`bodies against renal carcinoma, and that if all detect-
`able tumor is excised the antibody titer declines. "'
`The two patients these authors reported who had
`recurrent tumor did not show a decrease in antibody
`titer, and before the clinical detection of metastases,
`antibody titers actually increased. Another patient
`clinically free of tumor still has a high titer. The authors
`concluded that "persistence of elevated antibody titres
`(greater than 1 in 4) is correlated with the presence of
`occult persistent tumour." Patients with metastatic
`disease had high antibody titers when the disease was
`limited, and only when the tumor became widely
`disseminated did the titers markedly diminish or
`disappear.
`An inverse relationship between prognosis in cancer
`and peripheral
`lymphocyte counts has been de-
`scribed.:{' In their study of 18 patients with renal cancer,
`Morales and Eidinger'" showed a progressive decline in
`the absolute number of circulating lymphocytes and the
`T-cell population that paralleled the advance of the
`in
`malignant process. Kjaer'" has demonstrated
`patients with renal cancer that tumor directed, cell-
`mediated hypersensitivity is significantly increased
`after extensive washing of the leukocytes in vitro. This
`finding is consistent with the concept that coating of the
`migrating cells by a factor specifically inhibits their
`reactivity to tumor extracts. The effect was related to
`the tumor burden of the patients and seemed to be a
`in
`significant cause of
`immunologic nonreactivity
`patients with metastases. He suggests that the factor is
`probably circulating tumor antigen. In vitro assessment
`of cell-mediated immunity in renal cancer patients by
`Montie c t ti/.2!' showed greater inhibition of tumor cell
`growth in patients who had had nephrectomy.
`
`The large amount of immunologic data concerning
`renal cancer is not just of academic interest. Recent
`reports have suggested that immunotherapy may have
`a role in the treatment of metastatic renal carcinoma.
`Morales and Eidinger'l report that four of ten patients
`showed objective response of the metastatic disease
`(sites not stated) following bacillus Calmette-Guerin
`(BCG) immunotherapy. The BCG was given intrader-
`mally by a multiple puncture technique, weekly for six
`weeks, fortnightly for an additional four weeks, and
`thereafter monthly for an indefinite period. Side effects
`were mild. These authors have been sufficiently en-
`couraged to set up a prospective clinical trial. Xeno-
`geneic immune ribonucleic acid prepared from the
`spleens of sheep that had been injected with a renal
`cancer homogenate has been administered intrader-
`mally in 12 patients with extensive renal cancer.:gx
`There was no local or systemic toxicity, and although
`no patient has been treated for more than 16 months,
`the authors suggest that there has been some clinical
`prepared polymer particles
`benefit. Tykki ct t i / .
`from autologous tumor material. and these were mixed
`with tuberculin or cundittu trlhicurzs antigen as adju-
`vants. This resultant mixture was injected intrader-
`mally into 3 1 patients monthly after palliative nephrec-
`tomy. All patients had extensive renal carcinoma, and
`2 I had pulmonary secondaries. There was complete
`regression of pulmonary disease in six patients, though
`two of these had received progestogens, which are of
`proven value. The mode of action of progestogens is
`unlikely to be immunologic since they have been used
`as an alternative to prednisolone in suppressing re-
`jection of renal transplants.'" A recent further report of
`these patients showed that seven have survived 48 to
`70 months (median, 56 months), and five have no signs
`of carcinoma. The five-year survival of the immuno-
`therapy group is 23.6% and 4.3% for a "control" group
`of 21 patients who did not receive immunotherdpy. The
`differences are said to be statistically significant.4'
`M y personal experience is limited to a single case of
`a 23-year-old man who had extensive pulmonary and
`nodal metastases after nephrectomy for hyperne-
`phroma. His disease progressed unchecked by intra-
`dermal BCG, and no benefit was derived from subse-
`quent administration of progestogens or cytotoxic
`drugs.
`The treatment of disseminated renal cancer has been
`unrewarding, and a recent extensive review of the
`literature by Luderer et ul.21 has indicated the dis-
`appointingly small response rates-cytotoxic
`agents
`16% and progestogens 8%. Such regressions are for a
`short time. There are too few reports of response to
`immunotherapy for satisfactory conclusions to be
`drawn, and whether regressions are of material benefit
`
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`Breckenridge v. Novartis IPR2017-01592
`Fairlamb
`
`

`

`2106
`
`CAKCER April 15 1981
`
`Vol. 47
`
`to the patient remains to be seen. Further prospective
`trials of immunotherapy are needed, and since the
`likelihood of response depends largely on the body
`burden of tumor, anything that surgeons or radio-
`therapists can do to reduce this burden may be
`beneficial.
`
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`2. Bloom HJG. Regression of renal cancer. Canc,c,r 1973: 32:
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`3. Bloom HJG. Adjuvant therapy for adenocarcinoma of the
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`4. Boasberg PI). Eilber FR. Morton [>I,.
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`5 . Braren V. Taylor JN. Pace W. Regression of metastatic renal
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`8. Cole WH. Spontaneous regression of cancer: the metabolic
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`10. de Kernion JB, Ramming KP. Gupta RK. The detection and
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`I I . Deweerd JH, Hawthorne NJ. Adson MA. Regression of renal
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`12. Doolittle KH. Spontaneous remission of solitary bone
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`
`Breckenridge Exhibit 1135
`Breckenridge v. Novartis IPR2017-01592
`Fairlamb
`
`